CN102666526A - Indazole and pyrazolopyridine compounds as ccr1 receptor antagonists - Google Patents

Indazole and pyrazolopyridine compounds as ccr1 receptor antagonists Download PDF

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CN102666526A
CN102666526A CN2010800578454A CN201080057845A CN102666526A CN 102666526 A CN102666526 A CN 102666526A CN 2010800578454 A CN2010800578454 A CN 2010800578454A CN 201080057845 A CN201080057845 A CN 201080057845A CN 102666526 A CN102666526 A CN 102666526A
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alkyl
hydrogen
compound
naphthenic base
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B.N.库克
D.库兹米克
毛灿
H.拉扎维
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Boehringer Ingelheim International GmbH
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Abstract

Diclosed are CCRl receptor antagonists of the formula (I), wherein X is nitrogen or, C-R2; Ar1 is carbocycle, heteroaryl or heterocyclyl each optionally substituted by one to three Ra; Ar2 is carbocycle, heteroaryl or heterocyclyl, each optionally substituted by one to three Rb; Cyclic G is carbocycle, or heterocyclyl each optionally substituted by one to two R8; R1 is hydrogen, C1-6 alkyl or C 1-6 alkoxyC1-6 alkyl. Also disclosed are compositions, methods of making and using compounds of the formula (I).

Description

Indazole and Pyrazolopyridine compound as the CCR1 receptor antagonist
Request for data
The application requires the right of priority of the U.S. Provisional Application 61/253,590 of submission on October 21st, 2009.
Technical field
The present invention relates to contain aryl-or heteroaryl-carbocyclic amines and aryl-or the indazole and the Pyrazolopyridine of heteroaryl-heterocyclic amine; It can be used as the active antagonist of CCR1 and uses; And therefore can be used for treating through the activity mediation of CCR1 or multiple disease and the illness that continues; Comprise autoimmune disorder, for example rheumatoid arthritis and multiple sclerosis.The invention still further relates to the pharmaceutical composition that comprises these compounds, in multiple disease and treatment of conditions, use the method for these compounds, prepare the method for these compounds, and the midbody that is used for these methods.
Background technology
CCR 1 (CCR1) belongs to the extended familys (> 20 of chemoattracting cytoking (chemokine) acceptor); Itself and specificity chemokine (> 50) interact, with mediated leucocytes transportation, granule exocytosis effect, genetic transcription, mitogen effect and apoptosis.Chemokine is well-known because of the ability of its mediation substrate and inflammatory leukocytes transportation.At least three kinds of chemokines (MIP-1 α/CCL3, MCP3/CCL7 and RANTES/CCL5) are responsible for Inflamed tissue (Trebst etc., (2001) the American J of Pathology that monocyte, scavenger cell and TH1 cell are transported to rheumatoid arthritis (RA) and multiple sclerosis (MS) patient to the combination of CCR1 159P.1701).Macrophage inflammatory protein 1 α (MIP-1 α), scavenger cell chemical attractant albumen 3 (MCP-3) reach in the adjusting (RANTES) of normal T-cell expressing with the secretion activation and all come to light among the CNS MS patient, and come to light among MIP-1 α and the RANTES CNS in experiment autoimmunity encephalomyelitis (EAE) model of MS (Reviews:Gerard and Rollins (2001) Nature Immunology).Scavenger cell in RA patient's inflammation synovial membrane and Th1 cell also are the main producer of MIP-1 α and RANTES; It replenishes the synovial tissue of white corpuscle to RA patient continuously; To propagate chronic inflammatory diseases (Volin etc., (1998) Clin.Immunol.Immunopathology; Koch etc., (1994) J.Clin.Investigation; Conlon etc., (1995) Eur.J.Immunology).Suppose that the interaction between antagonism CCR1 and its chemokine ligand can block monocyte, scavenger cell and the Th1 cell chemotaxis to Inflamed tissue, thereby improve and the relevant chronic inflammatory diseases of autoimmune disorder (for example RA and MS).
For the evidence of CCR1, based on the disappearance and the small molecules antagonist of CCR1 gene in the development and the effect in the progress of the chronic inflammatory diseases (a kind of model of multiple sclerosis) relevant with experiment autoimmune encephalitis (EAE).The verified infectibility (55% pair 100%) and the seriousness (1.2 pairs 2.5) (Rottman etc., (2000) Eur J.Immunology) that reduces that can show the reduction of active EAE of CCR1 deficient mice.In addition, when with the administration of intravenously mode, give rat CCR1 is had the CCR1 small molecules antagonist of appropriate avidity (Ki=120nM), demonstration can postpone the outbreak of EAE and reduce its seriousness (Liang etc., (2000) J.Biol.Chemistry).With CCR1 part MIP-1 alpha specific antibody treatment mouse, also be proved through reducing and replenished, and prevented progress (Karpus etc., (1995) J.Immunology acute and recurrence EAE effectively to the T cell of CNS and the number of scavenger cell; Karpus and Kennedy (1997) J.Leukocyte Biology).Therefore, at least a CCR1 part has been proved can replenish white corpuscle to CNS, and in EAE, propagates chronic inflammatory diseases, and the effect of checking CCR1 in EAE and MS in the body further is provided.
The effect of CCR1 is also very important in the development of the chronic inflammatory diseases that the interior checking of body is relevant with RA and the propagation.For example, in the DBA/1 mouse, in the arthritis model due to the collagen (CIA), it is effective (Plater-Zyberk etc., (1997) Immunology Letters) that administration CCR1 antagonist has been proved reducing on synovial membrane inflammation and the destruction of joint.Another piece document description reduce effective antagonist (when oral giving) (Bioorganic and Medicinal Chemistry Letters 15 of the muroid CCR1 of seriousness (58%) in the joint caused inflammation of collagen (CIA) that LPS-quickens; 2005,5160-5164).The result from the Ib clinical trial phase that uses oral CCR1 antagonist who has delivered has confirmed the trend (Haringman etc., (2003) Ann.Rheum.Dis.) of the clinical improvements when not having adverse side effect.A patient of/3rd reached on symptoms of rheumatoid arthritis and symptom 20% improve (ACR20) at the 18th day, and the CCR1 positive cell is lowered in the patient's of treatment synovial membrane and reaches 70%, was accompanied by the remarkable reduction on particular cell types, was included in CD4 +Reduce by 50% in the T cell, at CD8 +Reduce by 50% in the T cell, and in scavenger cell, reduce by 34%.
The effect of CCR1 in MS and RA supported in some researchs (for example preceding text quote research), and the treatment theoretical basis that develops about the CCR1 antagonist is provided.
Summary of the invention
The present invention provides new compound, the interaction of its blocking-up CCR1 and its part, and therefore can be used for treating through the activity mediation of CCR1 or multiple disease and the illness that continues, comprise autoimmune disorder, for example rheumatoid arthritis and multiple sclerosis.The invention still further relates to the pharmaceutical composition that comprises these compounds, in various diseases and treatment of conditions, use the method for these compounds, prepare the method for these compounds, and the midbody that is used for these methods.
Detailed Description Of The Invention
Of the present invention the broadest general aspect in, it provides formula (I) compound or its pharmacy acceptable salt
Figure BDA00001782728400031
Wherein
X is nitrogen or C-R 2
Ar 1Be carbocyclic ring, heteroaryl or heterocyclic radical, it is respectively randomly by one to three R aReplace;
Ar 2Be carbocyclic ring, heteroaryl or heterocyclic radical, it is respectively randomly by one to three R bReplace;
Ring G is carbocyclic ring or heterocyclic radical, and it is respectively randomly by one or two R gReplace;
R 1Be hydrogen, C 1-6Alkyl or C 1-6Alkoxy C 1-6Alkyl;
R 2Be hydrogen or R a
R aBe C 1-6Alkyl, C 3-10Naphthenic base, C 1-6Alkoxyl group, C 1-6Alkylthio, C 1-6Alkyl sulphonyl, C 1-6Alkoxy carbonyl, amino, list-or two-C 1-6Alkylamino, C 3-6Cycloalkyl amino, C 1-6Alkyl amino-carbonyl, C 1-6Acyl group, C 1-6Acyl amino, C 1-6Dialkyl amino carbonyl, hydroxyl, halogen, cyanic acid, nitro, oxo, R 3-S (O) m-NH-, R 3-NH-S (O) m-, aryl or carboxyl;
R bFor hydroxyl, carboxyl, halogen ,-(CH 2) n-CN ,-(CH 2) n-CO 2C 1-6Alkyl, nitro ,-SO 3H, C 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl, C 3-10Naphthenic base, C 1-6Alkoxyl group, C 1-6Alkyl C (O)-,-(CH 2) n-NR cR d, R 3-S (O) m(CH 2) 0-1-, R 3-S (O) m-NR e-, R 3-NR e-S (O) m(CH 2) 0-1-,-NR f-C (O)-R e,-(CH 2) y-C (O)-(CH 2) n-NR cR d, heterocyclic radical, aryl or heteroaryl, each R bUnder possible situation randomly by halogenation or by 1 to 3 C 1-6Alkyl, hydroxyl, C 1-6Acyl group, C 1-6Alkoxy carbonyl, C 1-6Alkyl-S (O) m-, aryl or carboxyl substituted;
Each R c, R dBe hydrogen, C independently 1-6Alkyl, C 1-6Acyl group, C 3-10Naphthenic base, C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, cyanic acid-C 1-6Alkyl, C 1-6Alkyl C 1-6Alkoxyl group, C 1-6Alkyl sulphonyl, C 1-6Alkoxy carbonyl C 0-3Alkyl, C 1-6Alkoxy carbonyl C 3-10Naphthenic base ,-(CH 2) n-C (O)-NR eR fOr-(CH 2) n-NR eR f
Each R e, R fBe hydrogen, C independently 1-6Alkyl, C 3-10Naphthenic base, C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, list-or two-C 1-6Alkylamino C 1-6Alkyl, hydroxyl C 1-6Alkyl or C 1-6Acyl group;
R gBe C 1-6Alkyl, wherein said C 1-6Alkyl is randomly by partially or completely halogenation, C 2-6Thiazolinyl, carbocyclic ring, C 1-6Alkoxyl group, carbocylic radical-C 1-6Alkoxyl group, carbocylic radical-C 1-6Alkyl, hydroxyl C 1-6Alkyl, hydroxyl ,-(CH 2) n-CO 2C 1-6Alkyl or oxo;
R 3Be hydrogen, C 1-6Alkyl, C 3-6Naphthenic base, heterocyclic radical (CH 2) 0-1, single-or two-C 1-6Alkylamino, list-or two-C 1-6Alkylamino (CH 2) 2-3N (R e)-, aryl or heteroaryl, its each randomly by 1 to 3 C 1-6Alkyl, C 3-6Naphthenic base, C 1-6Alkoxyl group, halogen, hydroxyl, oxo, carboxyl ,-C (O) NR eR f, amino, single-or two-C 1-6Alkylamino, C 1-6Alkoxy carbonyl or C 1-6Acyl amino replaces;
Each n, y are 0-3 independently;
Each m is 0-2 independently.
The formula that preceding text provided (I) compound is provided in another embodiment of the invention, and wherein
Ring G is for randomly by one or two R gSubstituted carbocyclic ring;
The formula that preceding text provided (I) compound is provided in another embodiment of the invention, and wherein
X is a nitrogen;
Ar 1For randomly by one to three R aSubstituted carbocyclic ring;
Ar 2Be carbocyclic ring or heteroaryl, it is respectively randomly by one to three R bReplace;
R 1Be hydrogen;
R aBe C 1-3Alkyl, C 1-3Alkoxyl group, two-C 1-6Alkylamino, methyl sulphonyl, halogen or cyanic acid;
R bFor hydroxyl, carboxyl, halogen ,-(CH 2) n-CN ,-(CH 2) n-CO 2C 1-6Alkyl, nitro ,-SO 3H, C 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl, C 3-10Naphthenic base, C 1-6Alkoxyl group, C 1-6Alkyl C (O)-,-(CH 2) n-NR cR d, R 3-S (O) m(CH 2) 0-1-, R 3-S (O) m-NR e-, R 3-NR e-S (O) m(CH 2) 0-1-,-NR f-C (O)-R e,-(CH 2) y-C (O)-(CH 2) n-NR cR d, heterocyclic radical, aryl or heteroaryl, each R bUnder possible situation randomly by halogenation or by 1 to 3 C 1-6Alkyl, C 1-6Acyl group, C 1-6Alkoxy carbonyl, C 1-6Alkyl-S (O) m-, aryl or carboxyl substituted;
R 3Be hydrogen, C 1-6Alkyl, C 3-6Naphthenic base, heterocyclic radical (CH 2) 0-1, single-or two-C 1-6Alkylamino, list-or two- 1-6Alkylamino (CH 2) 2-3N (C 1-6Alkyl)-, aryl or heteroaryl, its each randomly by 1 to 2 C 1-6Alkyl, C 3-6Naphthenic base, C 1-6Alkoxyl group, halogen, hydroxyl, oxo, carboxyl ,-C (O) NR eR f, amino, single-or two-C 1-6Alkylamino, C 1-6Alkoxy carbonyl or C 1-6Acyl amino replaces.
The formula that preceding text provided (I) compound is provided in another embodiment of the invention, and wherein
Ar 1For by one or two R aSubstituted phenyl;
Ar 2For phenyl, thiadiazolyl group,
Figure BDA00001782728400051
Di azoly, pyrimidyl, furyl, thiazolyl or pyridyl, it is respectively randomly by one or two R bReplace;
Ring G is cyclopropyl or cyclobutyl;
R aBe halogen;
R bFor hydroxyl, carboxyl, halogen ,-CF 3,-CN ,-SO 3H, C 1-3Alkyl, C 3-6Naphthenic base C 1-3Alkoxyl group ,-(CH 2) n-CO 2C 1-3Alkyl ,-(CH 2) n-NR cR d, R 3-S (O) m(CH 2) 0-1-, R 3-S (O) 2-NR e-, R 3-NR e-S (O) 2(CH 2) 0-1-,-NR f-C (O)-R e,-(CH 2) y-C (O)-NR cR dOr morpholinyl;
Each R c, R dBe hydrogen, C independently 1-3Alkyl, C 1-3Acyl group, cyanic acid-C 1-3Alkyl, C 1-3Alkoxy carbonyl C 0-3Alkyl, C 1-3Alkoxy carbonyl C 3-6Naphthenic base or-(CH 2) n-C (O)-NR eR f
Each R e, R fBe hydrogen or C independently 1-3Alkyl;
R 3Be hydrogen or C 1-6Alkyl, it is respectively randomly by one or two C 1-6Alkoxyl group or oxo replace.
The formula that preceding text provided (I) compound is provided in another embodiment of the invention, and wherein
Ring G is a cyclopropyl;
R aFor-F or-Cl;
R bFor-CH 3, carboxyl ,-F ,-Cl ,-Br ,-I ,-CF 3, cyclopropyl ,-OCH 3,-CO 2Me ,-NR cR d,-CH 2-NR cR d, R 3-S (O) m-, R 3-S (O) 2-NR e-, R 3-NR e-S (O) 2-,-NR f-C (O)-R e,-C (O) NR cR dOr morpholinyl;
Each R c, R dBe independently hydrogen ,-CH 3,-C (O) CH 3,-CH 2CN, C 1-4Alkoxy carbonyl, methoxycarbonyl-C 1-2Alkyl-, methoxycarbonyl-C 3Naphthenic base-or-(CH 2)-C (O)-NR eR f
Each R e, R fBe independently hydrogen or-CH 3
R 3Be hydrogen or C 1-4Alkyl, its each randomly by one or two-OCH 3Or oxo replaces.
Formula (I) compound that in the broadest general embodiment, provides is provided in another embodiment of the invention, and wherein
X is C-R 2
Ar 1For randomly by one to three R aSubstituted carbocyclic ring;
Ar 2Be carbocyclic ring or heteroaryl, it is respectively randomly by one to three R bReplace;
Ring G is for randomly by one or two R gSubstituted carbocyclic ring;
R 1Be hydrogen;
R 2Be hydrogen or R a
R aBe C 1-3Alkyl, C 1-3Alkoxyl group, two-C 1-6Alkylamino, methyl sulphonyl, halogen or cyanic acid;
R bFor hydroxyl, carboxyl, halogen ,-(CH 2) n-CN ,-(CH 2) n-CO 2C 1-6Alkyl, nitro ,-SO 3H, C 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl, C 3-10Naphthenic base, C 1-6Alkoxyl group, C 1-6Alkyl C (O)-,-(CH 2) n-NR cR d, R 3-S (O) m(CH 2) 0-1-, R 3-S (O) m-NR e-, R 3-NR e-S (O) m(CH 2) 0-1-,-NR f-C (O)-R e,-(CH 2) y-C (O)-(CH 2) n-NR cR d, heterocyclic radical, aryl or heteroaryl, each R bUnder possible situation randomly by halogenation or by 1 to 3 C 1-6Alkyl, C 1-6Acyl group, C 1-6Alkoxy carbonyl, C 1-6Alkyl-S (O) m-, aryl or carboxyl substituted;
Each R c, R dBe hydrogen, C independently 1-6Alkyl, C 1-6Acyl group, C 3-10Naphthenic base, C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, cyanic acid C 1-6Alkyl, C 1-6Alkyl C 1-6Alkoxyl group, C 1-6Alkyl sulphonyl, C 1-6Alkoxy carbonyl C 0-3Alkyl, C 1-6Alkoxy carbonyl C 3-10Naphthenic base ,-(CH 2) n-C (O)-NR eR fOr-(CH 2) n-NR eR f
Each R e, R fBe hydrogen, C independently 1-6Alkyl, C 3-10Naphthenic base, C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, list-or two-C 1-6Alkylamino C 1-6Alkyl, hydroxyl C 1-6Alkyl or C 1-6Acyl group;
R 3Be hydrogen, C 1-6Alkyl, C 3-6Naphthenic base, heterocyclic radical (CH 2) 0-1, single-or two-C 1-6Alkylamino, list-or two-C 1-6Alkylamino (CH 2) 2-3N (C 1-6Alkyl)-, aryl or heteroaryl, its each randomly by 1 to 2 C 1-6Alkyl, C 3-6Naphthenic base, C 1-6Alkoxyl group, halogen, hydroxyl, oxo, carboxyl ,-C (O) NR eR f, amino, single-or two-C 1-6Alkylamino, C 1-6Alkoxy carbonyl or C 1-6Acyl amino replaces.
The formula that preceding text provided (I) compound is provided in another embodiment of the invention, and wherein
Ar 1For by one or two R aSubstituted phenyl;
Ar 2For phenyl, thiadiazolyl group,
Figure BDA00001782728400061
Di azoly, pyrimidyl, furyl, thiazolyl or pyridyl, its each randomly by one or two R bReplace;
Ring G is cyclopropyl or cyclobutyl;
R aBe C 1-3Alkyl, methyl sulphonyl, halogen or cyanic acid;
R bFor hydroxyl, carboxyl, halogen ,-CF 3,-CN ,-SO 3H, C 1-3Alkyl, C 3-6Naphthenic base C 1-3Alkoxyl group ,-(CH 2) n-CO 2C 1-3Alkyl ,-(CH 2) n-NR cR d, R 3-S (O) m(CH 2) 0-1-, R 3-S (O) 2-NR e-, R 3-NR e-S (O) 2(CH 2) 0-1-,-NR f-C (O)-R e,-(CH 2) y-C (O)-NR cR dOr morpholinyl;
Each R c, R dBe hydrogen, C independently 1-3Alkyl, C 1-3Acyl group, cyanic acid-C 1-3Alkyl, C 1-3Alkoxy carbonyl C 0-3Alkyl, C 1-3Alkoxy carbonyl C 3-6Naphthenic base or-(CH 2) n-C (O)-NR eR f
Each R e, R fBe hydrogen or C independently 1-3Alkyl;
R 3Be hydrogen or C 1-6Alkyl, it is respectively randomly by one or two C 1-6Alkoxyl group or oxo replace.
The formula that preceding text provided (I) compound is provided in another embodiment of the invention, and wherein
Ring G is a cyclopropyl;
R aFor-F or-Cl, methyl, methyl sulphonyl or cyanic acid;
R bFor-CH 3, carboxyl ,-F ,-Cl ,-Br ,-I ,-CF 3, cyclopropyl ,-OCH 3,-CO 2Me ,-NR cR d,-(CH 2)-NR cR d, R 3-S (O) m-, R 3-S (O) 2-NR e-, R 3-NR e-S (O) 2-,-NR f-C (O)-R e,-C (O) NR cR dOr morpholinyl;
Each R c, R dBe independently hydrogen ,-CH 3,-C (O) CH 3,-CH 2CN, C 1-4Alkoxy carbonyl, methoxycarbonyl-C 1-2Alkyl-, methoxycarbonyl-C 3Naphthenic base-or-(CH 2)-C (O)-NR eR f
Each R e, R fBe independently hydrogen or-CH 3
R 3Be hydrogen or C 1-4Alkyl, its each randomly by one or two-OCH 3Or oxo replaces.
Formula (I) compound that is applicable to the embodiment of preceding text according to each is provided in another embodiment of the invention, and wherein
Ring G is cyclopropyl or cyclobutyl.
The formula that preceding text provided (I) compound is provided in another embodiment of the invention, and wherein
Ring G is a cyclopropyl.
Formula (I) compound that is applicable to the embodiment of preceding text according to each is provided in another embodiment of the invention, and wherein
R cBe hydrogen or C 1-6Alkyl, and R dBe C 1-6Acyl group, cyanic acid-C 1-6Alkyl-, C 1-6Alkoxy carbonyl-C 0-3Alkyl-, C 1-6Alkoxy carbonyl C 3-10Naphthenic base or-(CH 2) n-C (O)-NR eR f
Each R e, R fBe hydrogen, C independently 1-6Alkyl.
Formula (I) compound that is applicable to the embodiment of preceding text according to each is provided in another embodiment of the invention, and wherein
Ar 2Be phenyl, pyrimidyl, furyl, thiazolyl or pyridyl, it is respectively randomly by one or two R bReplace;
R bFor-SO 2Me ,-I ,-Br ,-Cl ,-CF 3,-OMe ,-NMe 2,-CONHMe ,-SO 2NH 2
Formula (I) compound that is applicable to the embodiment of preceding text according to each is provided in another embodiment of the invention, and Ar wherein 2For
Figure BDA00001782728400081
Formula (I) compound that is applicable to the embodiment of preceding text according to each is provided in another embodiment of the invention, and wherein
R gFor
I) C 1-2Alkyl ,-CF 3, C 2Thiazolinyl, phenyl, C 1-4Alkoxyl group, carbocylic radical CH 2O-, carbocylic radical CH 2-,-CH 2OH, hydroxyl ,-CO 2C 1-4Alkyl or oxo;
Or
Ii) be methyl, vinyl ,-CF 3, phenyl ,-CH 2OH or hydroxyl.
Under classify representative compound of the present invention as, it can be through general synthetic schemes, embodiment and method as known in the art preparation.
Table I
Figure BDA00001782728400091
Figure BDA00001782728400101
Figure BDA00001782728400111
Figure BDA00001782728400121
Figure BDA00001782728400131
Figure BDA00001782728400141
Figure BDA00001782728400151
Figure BDA00001782728400161
Figure BDA00001782728400191
Figure BDA00001782728400201
(a)The HPLC-MS method sees also synthetic embodiment part.
(b)All compounds have all been reported [M+H] that observes +To bromine-containing compound, reported that two kinds of bromine isotopes observing (promptly 79Br with 81Br) [M+H] +
Or its pharmacy acceptable salt.
For disclosed all compounds of preceding text among the application, when name and structural hazard, should understand compound by organization definition.
The invention still further relates to pharmaceutical prepn, it contains one or more The compounds of this invention or its pharmaceutically acceptable derivates as active substance, optional with conventional vehicle and/or carrier combinations.
The compounds of this invention also comprises its form with isotropic substance mode mark.The isotropic substance mode mark pattern of the promoting agent of the present invention's combination is identical with this promoting agent; Except the following fact, one or more atoms of this promoting agent have been had atomic mass or total mass number and have been different from the natural atomic mass of atom or the one or more atom of total mass number found and replace.Be easy to commercial acquisition and can be according to the isotropic substance in the promoting agent that mixes the present invention's combination through good operation of setting up, the example comprises the isotropic substance of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example is respectively 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F reaches 36Cl.The promoting agent of the present invention's combination, its prodrug, or any pharmaceutically-acceptable salts, it contains other isotropic substance of the mentioned isotropic substance of one or more preceding text and/or other atom, thinks to comprise within the scope of the invention.
The present invention includes and use any above-claimed cpd that contains one or more unsymmetrical carbons, it can racemic modification and racemic mixture, single enantiomer, non-enantiomer mixture and the existence of indivedual diastereomer.Isomer will be defined as enantiomer and diastereomer.This isomeric form of all of these compounds, all in the present invention involved clearly.Each three-dimensional carbon (stereogenic carbon) can be R or S configuration, or the combination of configuration.
Some The compounds of this invention can exist to surpass a kind of tautomeric form.The present invention includes the method for using all these tautomers.
, otherwise think in patent specification that all terms that use in this article are general meaning, as known in the art only if statement is arranged in addition.For example, " C 1-4Alkoxyl group " for having the C of terminal oxygen 1-4Alkyl, for example methoxyl group, oxyethyl group, propoxy-, butoxy.Under the structurally possible situation, and unless otherwise, otherwise think that all alkyl, thiazolinyl and alkynyl are side chain or straight chain.Other defines as follows more specifically:
Carbocyclic ring comprises the hydrocarbon ring that contains three to 12 carbon atoms.These carbocyclic rings can be fragrance or non-aromatic ring system.That the non-aromatic ring system can be is single-or how unsaturated.Preferred carbocyclic ring includes but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, suberane base, cycloheptenyl, phenyl, indanyl, indenyl, benzocyclobutane base, dihydro naphthyl, tetralyl, naphthyl, decahydro naphthyl, benzocyclohepta alkyl and benzocyclohepta thiazolinyl.Some is about the term of naphthenic base, and for example tetramethylene base (cyclobutanyl) will use with cyclobutyl (cyclobutyl) convertibly.
Term " heterocycle " is meant stable non-fragrant 4-8 unit's (but being preferably 4 or 6 yuan) monocycle or non-fragrant 8-11 unit's dicyclo or Spirocyclic heterocyclic group, and it can be saturated or unsaturated.Each heterocycle comprises carbon atom, and one or more, preferred 1 to 4 heteroatoms that is selected from nitrogen, oxygen and sulphur.Heterocycle can connect through any atom of this ring, as long as form rock steady structure.
Should understand term " heteroaryl " and be meant fragrant 5-8 unit's monocycle or 8-11 unit dicyclo, it contains 1-4 heteroatoms, for example N, O and S.
Only if statement is arranged in addition, otherwise heterocycle and heteroaryl include but not limited to for example furyl, pyranyl, benzo Azoles base, benzothiazolyl, benzimidazolyl-, THP trtrahydropyranyl, dioxane base (dioxanyl), dioxolane base (dioxolanyl), tetrahydrofuran base,
Figure BDA00001782728400212
Azoles base, different
Figure BDA00001782728400213
Azoles base, thiazolyl, pyrazolyl, pyrryl, imidazolyl, thienyl, thiadiazolyl group, parathiazan base, 1,1-dioxo-1 λ 6-parathiazan base, morpholinyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolidyl, piperidyl, piperazinyl, purine radicals, quinolyl, dihydro-2H-quinolyl, isoquinolyl, quinazolyl, indazolyl, thieno-[2,3-d] pyrimidyl, indyl, pseudoindoyl, benzofuryl, benzopyranyl and benzodioxole base (benzodioxolyl).
The term " heteroatoms " that uses in this article be should understand and the atom beyond the carbon, for example O, N, S and P are meant.
In all alkyl or carbochain, one or more carbon atoms can be chosen wantonly by heteroatoms and replace: O, S or N are understood that; If N is not substituted; Then it is NH, it will also be appreciated that the alternative side chain of heteroatoms or straight chain carbon intrachain terminal carbon or inner carbon atom.This type of group can replace by some groups (for example oxo) as preamble is said, to obtain such as but not limited to the definition of alkoxy carbonyl, acyl group, amido and sulfo-(thioxo).
The term " aryl " that uses in this article be should understand and aromatic carbocyclic or heteroaryl are meant like this paper definition.Unless otherwise, otherwise each aryl or heteroaryl comprise that it is through partly or complete hydrogenant verivate.For example, quinolyl can comprise decahydroquinolyl and tetrahydric quinoline group, and naphthyl can comprise its hydrogenated derivatives, for example tetralyl.Other of aryl described in this paper and heteroaryl compound will be understood by those of ordinary skills through part or complete hydrogenant verivate.
" nitrogen " that uses in this article and " sulphur " comprise quaternized (quaternized) form of any oxidised form and any basic nitrogen of nitrogen and sulphur.For example, about-S-C 1-6Alkyl unless otherwise, otherwise thinks that it comprises-S (O)-C 1-6Alkyl and-S (O) 2-C 1-6Alkyl.
" alkyl " speech is meant the saturated fatty group that contains one to ten carbon atom or contains the list of two to 12 carbon atoms-or polyunsaturated fatty alkyl.Single-or the polyunsaturated fatty alkyl must contain at least one two keys or three key respectively." alkyl " is meant side chain and straight chained alkyl.Any combination term that it should be understood that use " alkane " or " alkyl " prefix is meant the analogue according to preceding text " alkyl " definition.For example, some terms, for example " alkoxyl group ", " alkylthio " are meant the alkyl that is linked to second group via oxygen or sulphur atom." alkyloyl " is meant through being linked to the alkyl of carbonyl (C=O).
Should understand when in patent specification, using, " halogen " speech is meant bromine, chlorine, fluorine or iodine, preferred fluorine." by halogenation ", " by part or halogenation fully "; " by partly or fluoridize fully "; The definition that " is replaced by one or more halogen atoms " comprises for example single, two or three halo derivatives on one or more carbon atoms.For alkyl, limiting examples is-CH 2CHF 2,-CF 3Deng.
It is optional through part or halogenation fully to understand each alkyl, carbocyclic ring, heterocycle or the heteroaryl described in this paper or its similar group.
The compounds of this invention is merely and is comprised " chemically stable ", such as those skilled in the art understanding.For example, the compound that has " dangling bonds (dangling valency) " or " carbanion " is not the included compound of the inventive method disclosed herein.
The present invention includes the pharmaceutically acceptable derivates of formula (I) compound." pharmaceutically acceptable derivates " is meant any pharmacy acceptable salt or ester; Or any other compound that when giving the patient, can provide (directly or indirectly) to can be used for compound of the present invention, or the residue of the meta-bolites of its tool pharmacological activity or tool pharmacological activity.The meta-bolites that should understand the tool pharmacological activity is meant can be with enzyme mode or chemical mode by any The compounds of this invention of biological metabolism.It comprises the derivative compound through hydroxylation or oxidation for example of the present invention.
Pharmacy acceptable salt comprises the salt that forms derived from pharmaceutically acceptable inorganic and organic bronsted lowry acids and bases bronsted lowry.The instance that is fit to acid comprises hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, crosses chloric acid, fumaric acid, toxilic acid, phosphoric acid, oxyacetic acid, lactic acid, Whitfield's ointment, succsinic acid, right-toluene-sulfonic acid (toluene-p-sulfuric), tartrate, acetic acid, Hydrocerol A, methylsulfonic acid, formic acid, phenylformic acid, propanedioic acid, naphthalene-2-sulfonic acid (naphthalene-2-sulfuric) and Phenylsulfonic acid.Other acids, for example oxalic acid though itself be not pharmaceutically acceptable, can be used to prepare the salt as midbody, to obtain compound and pharmaceutically-acceptable acid addition thereof.Salt derived from being fit to alkali comprises basic metal (for example sodium), earth alkali metal (for example magnesium), ammonium and N-(C 1-C 4Alkyl) 4 +Salt.
In addition, use the prodrug of The compounds of this invention within the scope of the invention.When being included in simple chemical conversion, modifies prodrug, to produce the compound of The compounds of this invention.Simple chemical conversion comprises hydrolysis, oxidation and reduction.Particularly, when prodrug was given the patient, this prodrug can be converted into the disclosed compound of preceding text, through to give desired pharmacological effect.
Formula I compound can use general compound method preparation hereinafter described, and it also constitutes some of the present invention.
General compound method
The present invention also provides the method for preparation I compound.The compounds of this invention can be through general method and the embodiment that hereinafter proposed, and those of ordinary skills institute is known and chemical literature in institute's method of reporting preparation.
Unless otherwise, otherwise solvent, temperature, pressure and other reaction conditions can easily select by those of ordinary skills.Concrete operations are provided in the synthetic embodiment part.
Aryl-or heteroaryl-Cycloalkyl amine midbody or for commercially available getting can be according to general operation or following reference (its integral body being incorporated herein by reference at this) preparation, or can use disclosed method preparation in the chemical literature by those skilled in the art.
Aryl-or heteroaryl-cyclopropylamine can be Cyclopropanated and synthetic through the reductibility of alkyl titanium oxide mediation by corresponding aryl or heteroaryl nitrile, wherein uses Grignard reagent (Szymoniak, people such as J., J.Org.Chem.2002; 67,3965 and Bertus, people such as P., J.Org.Chem.2003; 68,7133) or zincon (de Meijere, people such as A.; Org.Lett.5,2003,753).Perhaps, aryl-cyclopropylamine can be from aryl nitrile or aryl ester through cycloalkylation (Jonczyk for example, people such as A., Org.Prep.Proc.27; 1995,355), then through this nitrile or ester group are converted into carboxylic acid; The gained carboxylic acid is carried out Ke Erdisi to be reset (Curtius rearrangement) and becomes carbamate (Hanano for example, people such as T., Bioorg.Med.Chem.Lett.10; 2000,881), and with gained carbamate deprotection synthesize.
The formation of amido linkage can carry out through standard coupling condition well known in the art (Bodanszky M. for example, The Practice of Peptide Synthesis, Springer-Verlag:1984 is incorporated herein by reference its integral body at this), for example through in the presence of 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (EDC) and I-hydroxybenzotriazole, with carboxylic acid and amine reaction.Reaction process can be through for example tlc (TLC) monitoring of conventional method.Midbody and product can be through method as known in the art (comprising column chromatography, HPLC or recrystallization) purifying.
Method described in hereinafter and the synthetic embodiment part can be used for preparing formula Ia compound (promptly wherein X is the formula I compound (reaction equation I, II and III) of nitrogen), and formula Ib compound (promptly wherein X is C-R 2Formula I compound (reaction equation IV and V)).Hereinafter in the reaction equation, Ar 1, Ar 2, ring G, X, R 1And R 2All has defined implication in the detailed description of formula I compound.
Formula Ia compound can prepare according to reaction equation I-III.
Reaction equation I
Shown in reaction equation I, can be with having Ar 1Suitable formula III hydrazine (free alkali or suitable salt form, for example hydrochloride) and 3,5-two bromo-4-pyridylaldehyde II reaction, this existence that is reflected at sodium acetate down and in suitable solvent (for example EtOH), carry out obtain formula IV hydrazone.Can the cyclisation of formula IV compound be obtained formula V compound, this cyclisation is at suitable reagent (two amine ligands (for example trans-N, N '-dimethyl cyclohexane-1,2-diamines), mantoquita (for example CuI), alkali (K for example for example 2CO 3) and solvent (for example N-N-methyl-2-2-pyrrolidone N-)) existence under carry out.At suitable cross coupling reagent (Pd catalyzer (Pd (PhCN) for example for example 2Cl 2), part [for example 1, two (diphenylphosphine) ferrocene (dppf) of 1-], alkali (Et for example 3N) and solvent (for example toluene)) existence under, under the CO atmosphere of pressurization (be preferable over about 15 crust), can be in sealed pressure vessel the amine of this bromo-azaindazole V and suitable formula VI be heated jointly, obtain required formula Ia compound.
Reaction equation II
Figure BDA00001782728400261
Perhaps, formula Ia compound can be synthetic according to the general operation shown in the reaction equation II.Formula V bromo-azaindazole can be under pressurization CO atmosphere; In the presence of above-mentioned suitable Pd catalyzer, part and alkali; In absolute ethyl alcohol, heat; Obtain formula VII ethyl ester, its available suitable hydroxide bases (for example KOH) hydrolysis in suitable solvent systems (for example methanol aqueous solution) obtains formula VIII carboxylic acid.Under the acid amides coupling condition known in the art, carboxylic acid VIII can react with suitable formula VI amine.For example; Acid VIII can use suitable activating reagent to handle; Said activating reagent is sulfur oxychloride, oxalyl chloride, (benzotriazole-1-base oxygen base) tripyrrole alkyl phosphorus
Figure BDA00001782728400262
hexafluorophosphate (PyBOP), O-(7-pyridine and triazol-1-yl)-N for example; N; N '; N '-tetramethyl-urea
Figure BDA00001782728400263
hexafluorophosphate (HATU), O-(benzotriazole-1-yl)-N; N; N '; N '-tetramethyl-urea
Figure BDA00001782728400264
hexafluorophosphate (HBTU) or O-(benzotriazole-1-yl)-N; N, N ', N '-tetramethyl-urea
Figure BDA00001782728400265
a tetrafluoro borate (TBTU); Said processing is at suitable formula VI amine, suitable alkali (for example triethylamine or N; The N-diisopropylethylamine) under the existence, in suitable solvent (for example N or N-Methyl pyrrolidone), carries out, obtain required formula Ia compound.
The reactional equation formula III
Figure BDA00001782728400271
Perhaps, formula VIII carboxylic acid can prepare based on the synthetic order shown in the reactional equation formula III.Formula II compound can with suitable formula III hydrazine (free alkali or suitable salt form; Hydrochloride for example) reaction; Polar aprotic solvent (for example NMP, DMF, DMAC or DMPU) is used in this reaction; In the presence of alkali (for example the KOH aqueous solution, the NaOH aqueous solution, the LiOH aqueous solution, the CsOH aqueous solution, NaOMe, NaOEt, KOt-Bu or KOt-amyl), (preferably at about 80 ° of C) carry out in suitable temperature, obtain formula V compound.Bromo-azaindazole V can with suitable Grignard reagent (for example R-MgCl, wherein R can be selected from sec.-propyl, normal-butyl, sec.-butyl and cyclohexyl) and CO 2, at suitable polar aprotic solvent (for example THF, MTBE, Et 2O, DME or two Alkane) in, in suitable reaction temperature (preferably at about-20 ° of C) reaction, obtain formula VIII carboxylic acid, it can be converted into above-mentioned formula Ia compound.
Formula Ib compound can be shown in reaction equation IV and V and is prepared.In these reaction equations, Ar 1, Ar 2, G, X, R 1And R 2, all have defined implication in the detailed description of formula I.
Reaction equation IV
Figure BDA00001782728400281
Shown in reaction equation IV, formula IX indazole-4-formic acid can be coupled to suitable formula VI amine, and this coupling uses amido linkage coupling condition well known in the art (for example above-mentioned condition) to carry out.Gained indazole-4-methane amide can react with suitable formula XI aryl halide; This is reflected in the chemical literature and carries out under the known cross coupling condition; For example at suitable temperature (preferably at about 120 ° of C), at suitable reagent (catalyzer (for example CuI), alkali (K for example for example 2CO 3) and part (for example racemize trans-N, N '-dimethyl cyclohexane-1,2-diamines)) existence under, in suitable solvent (for example DMF) heating, obtain formula Ib compound.
Perhaps, formula Ib compound can be shown in reaction equation V and is synthesized.
Reaction equation V
Figure BDA00001782728400291
Formula IX indazole-4-formic acid can be converted into its corresponding formula XII manthanoate, and this conversion uses enzymatic synthesis condition well known in the art to carry out, and for example uses the trimethyl silyl diazomethane in suitable solvent systems (for example methyl alcohol and toluene), to handle.Ester XII can react with suitable formula XI aryl halide, and this is reflected under the above-mentioned cross coupling condition and carries out, and obtains formula XIII indazole-4-manthanoate; Said formula XIII indazole-4-manthanoate can be converted into formula XIV acid, and this conversion is under the standard hydrolysis condition, to carry out, and for example uses suitable alkali (for example NaOH) in suitable aqueous solvent system (for example water and methyl alcohol), to handle.Of preamble, formula XIV acid can acid amides coupling condition known in the art under through with amine VI reaction conversion be formula Ib compound.
Can further be converted into other formula I compound through the formula I compound of method for preparing, this conversion is carried out by means commonly known in the art, and is illustrated in following synthetic embodiment part.
Hereinafter (being reaction equation VI-IX) and the described method of synthetic embodiment part can be used for preparing midbody VI, and this midbody can be used for preparation I compound.In the reaction equation below, ring G, Ar 2And R bAll has defined implication in the detailed description of formula I compound.
Formula VIa midbody (i.e. Ar wherein 2Be 1,3, the formula VI midbody of 4-thiadiazoles) can prepare according to reaction equation VI.
Reaction equation VI
Figure BDA00001782728400301
Shown in reaction equation VI; Wherein PG be appropriate protection base (for example Cbz) formula XV amino acid can with the hydrazine XVI coupling through Boc protection; This coupling uses amido linkage coupling condition well known in the art (for example above-mentioned condition) to carry out, and obtains the hydrazides XVII through the Boc protection.Formula XVII compound can with lawesson reagent (Lawesson ' s reagent) reaction; This is reflected under the existence of suitable solvent (for example toluene); With carry out in suitable temperature (for example at about 90 ° of C); Obtain corresponding thio-hydrazide through the Boc protection; It can use suitable acid (for example two of 4N HCl
Figure BDA00001782728400302
alkane solution) deprotection, obtains the suitable salt form (for example hydrochloride) of thio-hydrazide XVIII.Formula XVIII compound can react with DMF, and this is reflected at suitable reagent (diethyl chloro-phosphate XIX and suitable alkali (Et for example for example 3N)) carry out under the existence, obtain corresponding 1,3, the 4-thiadiazoles, its available suitable reagent (the for example acetic acid soln of 48%HBr) carries out the N-deprotection, obtains the midbody of formula VIa.
In addition, formula VIb midbody (i.e. Ar wherein 2Be 1,2,4- The formula VI midbody of diazole) can prepare according to reaction equation VII.
Reaction equation VII
Figure BDA00001782728400312
Shown in reaction equation VII; The formula XV amino acid of appropriate protection (is that PG is suitable protection base; Cbz for example) can be converted into corresponding amide XX; This transform to use standard amide key coupling condition (for example above-mentioned condition), and in the presence of suitable ammonium salt (for example volatile salt), suitable alkali (for example Et3N) and suitable solvent (for example DMF), carries out.Formula XX acid amides can react with suitable dehydrated reagent (for example cyanuryl chloride), and this is reflected under the existence of suitable solvent (for example DMF), and (for example at about 0 ° of C to 30 ° of C) carries out in suitable temperature, obtains formula XXI nitrile.Compounds X XI can react with hydroxylamine hydrochloride, and this is reflected under the existence of suitable alkali (for example salt of wormwood), and in suitable solvent (for example ethanol), (for example at about 79 ° of C) carry out in suitable temperature, obtain formula XXII compound.Amidoxim XXII can with suitable formula XXIII carboxylic acid reaction; Amido linkage coupling reagent well known in the art (for example CDI) is used in this reaction; Carry out at suitable solvent (for example DMF) with under appropriate condition (for example in about 100 ° of C heating); Obtain corresponding 1,2,4-
Figure BDA00001782728400313
oxadiazole derivative; It can carry out the N-deprotection as stated, obtains formula VIb midbody.
Formula VIc midbody (i.e. Ar wherein 2Be 1,2,4-
Figure BDA00001782728400321
The formula VI midbody of other positional isomers of diazole) can prepare according to reaction equation VIII.
Reaction equation VIII
Figure BDA00001782728400322
Formula XXIV amidoxim can be under above-mentioned appropriate condition, is formed in corresponding nitrile and prepares through azanol is added.Shown in reaction equation VIII; Amidoxim XXIV can be the formula XV amino acid reaction of suitable protection base (for example Boc) with PG wherein; This reaction utilizes suitable amide coupling reagent (for example CDI); At suitable solvent (for example DMF); With under appropriate condition (for example in about 100 ° of C heating), carry out; Obtain corresponding 1,2,4-
Figure BDA00001782728400323
diazole; It can be under appropriate condition, and (for example with suitable acid (for example two of 4N HCl
Figure BDA00001782728400324
alkane solution) reaction) through the N-deprotection, obtains formula VIc midbody.
Formula VId midbody (i.e. Ar wherein 2Formula VI midbody for pyrimidine) can prepare according to reaction equation IX.
Reaction equation IX
Figure BDA00001782728400331
Shown in reaction equation IX; (wherein PG is suitable protection base to the amino formonitrile HCN of the formula XXI of appropriate protection; Boc for example) can be converted into corresponding amidine hydrochloride XXV, this transform through with suitable reagent (the for example ethanolic soln of sodium ethylate) reaction, carry out with ammonium chloride and WITH AMMONIA TREATMENT then.In synthetic conversion the independently, 3-dimethylamino propenal XXVI can use suitable reagent (Br for example 2And NIS), at suitable solvent (CHCl for example 3) middle halogenation, the 2-halo-3-dimethylamino propenal that obtains formula XXVII (is R bBe Br or I).Subsequently, amidine hydrochloride XXV can react with formula XXVII compound, and this is reflected in the suitable solvent (for example EtOH), and (for example at about 80 ° of C) carry out in suitable temperature, obtain formula XXVIII pyrimidine.Compounds X XVIII can use well known in the art and above-mentioned condition to carry out the N-deprotection, obtains formula VId midbody.
The formula XV amino acid of appropriate protection can be used for the synthetic of formula VI midbody; Said formula XV amino acid or for commercially available getting; Can prepare according to general operation or following reference (its integral body being incorporated herein by reference), or can use disclosed method preparation in the chemical literature by those skilled in the art at this.
3-tert-butoxycarbonyl amino-trimethylene oxide-3-formic acid can be according to the disclosed operation preparation of patented claim WO2009/070485A1.
Below for the instance of the commercially available alpha-non-natural amino acid that gets.These instances are used to support the purpose of embodiment of the present invention, and the scope that is construed as limiting the invention absolutely not.Amino acid whose suitable protection can carry out through standard condition well known in the art (for its more complete enumerating, referring to Greene, T.W.; Wuts, P.G.M. Protective Groups in Organic Synthesis, 3rd Ed, Wiley, New York, 1999, it is incorporated herein by reference in this integral body).
Figure BDA00001782728400341
Synthetic embodiment
General method: only if point out in addition, otherwise all are reflected at ambient operation.All compounds all characterize through following method is at least a: 1H NMR, HPLC, HPLC-MS and fusing point.
The MS data of being reported are [M+H] that is observed +For bromine-containing compound, one or both bromine isotopes have been reported (promptly 79Br with 81Br) [M+H] +
Use one of following method in Table I, to report RT (RT):
Figure BDA00001782728400351
Figure BDA00001782728400361
Synthesizing of midbody
Following heteroaryl-cyclopropylamine midbody or the synthetic of its corresponding salt form are disclosed among the patented claim WO 2009/070485A1:
Figure BDA00001782728400362
* intermediate can use disclosed operation in suitable reagent and the reference paper based on related analogs and prepare.
Synthesizing of embodiment 1:1-(4-fluorophenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid (1)
Figure BDA00001782728400371
In the 1L flask, pack 3 into, 5-dibromo pyridine-4-formaldehyde (50.0g, 189mmol, 1.0 equivalents) and 4-fluorophenyl hydrazonium salt hydrochlorate (31.0g, 191mmol, 1.01 equivalents).The NMP (250mL) that packs into, and the gained slurries stirred 2 hours in envrionment temperature.With 85%KOH sheet (27.4g, 415mmol, 2.2 equivalents) and water (27.4mL) the preparation KOH aqueous solution, and this KOH solution packed in this reaction mixture.This batch of material is heated to 80 ° of C, and kept 30-60 minute in this temperature.Then at 80 ° of C water (250mL) of packing into, and the gained slurries were cooled to envrionment temperature through 4-16 hour.Filter this slurries, with this solid of water washing, and under vacuum, dry, obtain 4-bromo-1-(4-fluorophenyl)-1H-pyrazolo [3,4-c] pyridine, it is a solid.
4-bromo-1-(4-fluorophenyl)-1H-pyrazolo [3,4-c] pyridine (50.0g, 171mmol, 1 equivalent) and THF (300mL) packs in the 1L flask.These slurries are cooled to-20 ° of C.With the speed that keeps temperature to be lower than-10 ° of C i-PrMgCl solution (128.2mL, 256.4mmol, the THF solution of 2.0M, 1.5 equivalents) of packing into.This is reflected at-10 ° of C and kept 3 hours.With CO 2The gas bubbling is gone into this reaction mixture and is risen to peak value up to temperature, and temperature begins to descend then.With temperature regulation to 22 ° C, and add i-PrOAc (325mL).With the dense HCl (55mL) and water (195mL) the preparation HCl aqueous solution.This HCl solution of about 10mL is packed in this reaction mixture, and reaching pH is 6-7.Then with this mixture heating up to 55 ° C, and the HCl solution of the remaining about 240mL that packs into.Should react warp and be cooled to envrionment temperature in 1 hour, keep 1 hour, and filter in this temperature.Water and this solid of i-PrOAc washing are dried under vacuum, obtain title compound, and it is a solid.
Synthesizing of embodiment 2:1-(4-fluoro-phenyl)-1H-indazole-4-formic acid (2)
Figure BDA00001782728400381
(2.00g 12.3mmol) is suspended in methyl alcohol (20mL) and the toluene (30mL) with indazole-4-formic acid in room temperature.Slowly add 2M trimethyl silyl diazomethane toluene solution (12mL, 24mmol), and with this mixture in stirring at room up to this solution becomes yellowly.Stop this reaction also in a vacuum except that desolvating with spirit acid (5mL).Resistates with the gradient elution of the 0-30% ETHYLE ACETATE in the hexane, obtains 1H-indazole-4-methyl-formiate through the silica gel chromatography purifying.
Room temperature with 1H-indazole-4-methyl-formiate (5.0g, 28mmol), cuprous iodide (5.7g, 3.0mmol), salt of wormwood (4.15g, 30.0mmol) (3.47g, pack in the ST with 4-fluorine iodobenzene by mixture 30.0mmol).This pipe is vacuumized, with the argon gas backfill and add N (20mL), add racemize-trans-N then, N '-dimethyl cyclohexane-1, the 2-diamines (0.93g, 6.5mmol).Stir this solution 3 hours at 120 ° of C, be cooled to room temperature then, and water (50mL) and ETHYLE ACETATE (80mL) dilution.Separate organic layer,, and use dried over sodium sulfate with salt solution (30mL) washing.Filter crude product, concentrate, and,, obtain 1-(4-fluoro-phenyl)-1H-indazole-4-methyl-formiate with the gradient elution of the 0-30% ETHYLE ACETATE in the hexane through the silica gel chromatography purifying.
(2.0g 7.4mmol) adds 2N sodium hydroxide solution (10mL) in the solution in water (20mL) and methyl alcohol (20mL) to 1-(4-fluoro-the phenyl)-1H-indazole-4-methyl-formiate that stirs.With this vlil 1 hour.This solution is cooled to room temperature, and uses 1N HCl acidified aqueous solution to be 3-4 to pH.Filter this mixture, and, obtain 1-(4-fluoro-phenyl)-1H-indazole-4-formic acid with MeOH (30mL) washing gained solid and dry.
Synthesizing of the two trifluoroacetates (3) of embodiment 3:1-(6-bromo-pyridin-3-yl)-cyclopropylamine
Under Ar atmosphere, the anhydrous THF (750mL) that in the 2L round-bottomed flask of being furnished with mechanical stirrer of oven drying, packs into, Ti (Oi-Pr) then packs into 4(72.8mL, 246mmol).Under Ar, purge this solution and be heated to 50 ° of C.With 6-bromo-cigarette nitrile (30.0g 164mmol) adds this mixture, drip then (through 40 minutes) 1M ethylmagnesium bromide THF solution (410mL, 410mmol).Stirring at 50 ° of C should reaction.After 3 hours, this reaction mixture is cooled to room temperature, and adds the 3M HCl aqueous solution (approximately 350mL).This mixture is transferred in the separating funnel, and with ether (3 * 500mL) washings.With the water layer hold over night.Use then the 2M NaOH aqueous solution with water layer alkalize to pH be 10.Dilute this solution with EtOAc (500mL), and vigorous stirring gained solution 5 minutes.Leave standstill this solution and slowly layering.The decant organic layer, and identical extracting operation repeats twice.Merge organic layer, with salt solution (50mL) washing, through MgSO 4Dry and concentrated in a vacuum, obtain oily matter.This bullion oily matter uses CH through the silica gel chromatography purifying 2Cl 2In the gradient elution of 0-10%MeOH, obtain 1-(6-bromo-pyridin-3-yl)-cyclopropylamine, it is an oily matter, its slow crystallization (ES+m/z 213.3,215.3).
With 1-(6-bromo-pyridin-3-yl)-(1.16g 4.60mmol) is dissolved in CH to cyclopropylamine 2Cl 2(20mL).Add Et successively 3N (0.78mL, 5.6mmol) and Boc 2O (1.11g, 5.10mmol), and should reaction in stirring at room.After 20 hours, CH is used in this reaction 2Cl 2(20mL) and water (20mL) dilution, and layering.Water layer is used CH 2Cl 2(100mL) extraction.With the CH that merges 2Cl 2Layer is used brine wash, through MgSO 4Drying is filtered and is concentrated, and obtains [1-(6-bromo-pyridin-3-yl)-cyclopropyl]-t-butyl carbamate, and it is a solid.
(0.800g 2.55mmol) is dissolved in CH with [1-(6-bromo-pyridin-3-yl)-cyclopropyl]-t-butyl carbamate 2Cl 2(10mL).Drip TFA (5mL).After 4 hours, should react concentrated in a vacuum, and obtain title compound, it is oily matter (ES+m/z 213.1,215.1).
Synthesizing of embodiment 4:1-(5-bromo-pyrimidine-2-base)-cyclopropylamine dihydrochloride (4)
Figure BDA00001782728400401
(50mL 500mmol) is dissolved in CHCl with 3-dimethylamino-propenal in room temperature 3(400mL).Through syringe slowly added through 5 minutes bromine (25.7mL, 0.500mol).After 30 minutes, this reaction is poured into 200mL Na 2S 2O 3Saturated aqueous solution and 200mL NaHCO 3In the mixture of saturated aqueous solution, and use CH 2Cl 2(3 * 100mL) extract this mixture.With the organic layer that merges through MgSO 4Dry and the concentrated solid that obtains.This solid is dissolved among the EtOAc (200mL), leaches insolubles, concentrated filtrate in a vacuum, and be used in 50% solution washing gained solid in the hexane, and obtaining 3-dimethylamino-2-bromo-propenal, it is solid (ES+m/z 178.28).
With (1-amidino-cyclopropyl)-t-butyl carbamate hydrochloride (1.0g; 4.2mmol) (1.1g is 6.4mmol) among the EtOH (2mL) in the adding pressure tube for (according to disclosed operation preparation among the patented claim WO 2009/070485A1) and 3-dimethylamino-2-bromo-propenal.This reaction vessel is built, and this mixture was heated 24 hours at 80 ° of C.This mixture is cooled to room temperature, and adds methyl alcohol (20mL).Filter the gained solid, and concentrated filtrate in a vacuum.Resistates is dissolved in CH 2Cl 2(50mL), and solids filtered.Concentrated filtrate, resistates use the gradient elution of the 0-50%EtOAc in the hexane through the silica gel chromatography purifying, obtain [1-(5-bromo-pyrimidine-2-base)-cyclopropyl]-t-butyl carbamate, and it is a solid.
(1.18g 3.76mmol) is dissolved in CH with [1-(5-bromo-pyrimidine-2-base)-cyclopropyl]-t-butyl carbamate in room temperature 2Cl 2(5mL).Two
Figure BDA00001782728400402
of adding 4M HCl and alkane solution (9.4mL, 38mmol).After 2 hours, through N 2Air-flow removes and desolvates, and obtains the bullion title compound, and it is a solid, its not purified direct use (ES+m/z 216.3).
Embodiment 5: [1-(5-iodo-furans-2-yl)-cyclopropyl]-t-butyl carbamate (5) synthetic
Figure BDA00001782728400411
In room temperature to (1-furans-2-base-cyclopropyl)-t-butyl carbamate (4.30g; 19.3mmol) disposable adding solid N-iodosuccinimide in (according to disclosed operation preparation among the patented claim WO 2009/070485A1) solution in dry DMF (77mL) (4.77g, 21.2mmol).2.5 after hour, Na is used in this reaction 2S 2O 3Saturated aqueous solution (75mL), water (75mL) and ether (100mL) dilution.Be separated, and water layer is with ether (2 * 100mL) extractions.With the organic layer that merges through Na 2SO 4Dry and concentrated.The gained solid grinds with hexane, obtains title compound, and it is powder (ES+m/z 350.5).
Synthesizing of embodiment 6:3-(1-amino-cyclopropyl)-oil of Niobe (6)
Figure BDA00001782728400412
(0.600mL 8.46mmol) adds in the methyl alcohol (15mL), and this solution is warmed to room temperature with Acetyl Chloride 98Min. at 0 ° of C.Stir after 20 minutes, (0.500g is 2.82mmol) also with this reaction mixture reflux to add the amino cyclopropyl-phenyl formic acid of 3-.After 16 hours, under 65 ° of C nitrogen gas stream, concentrate this mixture.Resistates neutralizes with saturated aqueous solution of sodium bicarbonate (50mL), and with ETHYLE ACETATE (3 * 50mL) extractions.With the organic layer that merges with brine wash (100mL), through MgSO 4Drying is filtered and is concentrated, and obtains the bullion title product, its not purified direct use.
Synthesizing of embodiment 7:1-(2-bromo-pyridin-4-yl)-cyclopropylamine trifluoroacetate (7)
Figure BDA00001782728400421
To (2-bromo-the pyridin-4-yl)-methyl alcohol that stirs at 0 ° of C (3.00g, 16.0mmol) and N, the N-diisopropylethylamine (8.3mL, 48mmol) add in the solution in methylene dichloride (30mL) methylsulfonyl chloride (1.30mL, 16.8mmol).The gained mixture is warmed to room temperature.After 1 hour, with this mixture with methylene dichloride (20mL) dilution, and with ammonium chloride saturated aqueous solution (3 * 10mL), saturated aqueous solution of sodium bicarbonate (10mL), salt solution (10mL) wash, through MgSO 4Drying is filtered and is concentrated, and obtains bullion methylsulfonic acid 2-bromo-pyridin-4-yl methyl esters, its not purified direct use.
(4.24g, (1.02g is 15.1mmol) in the solution of the mixture of ethanol (30mL) and water (6mL) for the Potssium Cyanide that 15.9mmol) add to stir with methylsulfonic acid 2-bromo-pyridin-4-yl methyl esters in room temperature.After 72 hours, add ETHYLE ACETATE (80mL) and saturated aqueous solution of sodium bicarbonate (40mL), and be separated.(3 * 40mL) washings are through MgSO for the organic layer water 4Drying is filtered and is concentrated.The gained resistates is through the silica gel chromatography purifying, and the gradient elution with the 0-60% ETHYLE ACETATE in the heptane obtains that (2-bromo-pyridin-4-yl)-(ES+m/z 197.41 for acetonitrile; 199.40).
With (2-bromo-pyridin-4-yl)-acetonitrile (1.20g, 6.09mmol) and glycol dibromide (0.663mL is 7.61mmol) at anhydrous Et 2Solution in the mixture of O (5mL) and anhydrous DMSO (1mL) is added to NaH, and (60% is scattered in the Dormant oils; 585mg; 14.6mmol) in the suspension in anhydrous DMSO (10mL), cool off through water-bath simultaneously and control the heat that is generated, and with the gained mixture in stirring at room.After 18 hours, add entry (10mL) and ETHYLE ACETATE (10mL), be separated, and water layer is with ETHYLE ACETATE (3 * 10mL) extractions.The organic layer that merges is washed with salt solution (30mL), and through MgSO 4Drying is filtered and is concentrated.Resistates is through SiO 2Purifying with the gradient elution of the 0-60% ETHYLE ACETATE in the heptane, obtains 1-(2-bromo-pyridin-4-yl)-Trimetylene formonitrile HCN, and it is that (ES+m/z 223.36 for solid; 225.39).
(1.16g 5.20mmol) adds DIBAL-H (10.4mL, the toluene solution of 1M) in the solution in toluene (30mL) to 1-(2-bromo-pyridin-4-yl)-Trimetylene formonitrile HCN at-78 ° of C.At-78 ° of C this mixture was stirred 1 hour, and be warmed to room temperature.After 1 hour, add ETHYLE ACETATE (30mL), add 1M H then 2SO 4The aqueous solution (30mL).Be separated, and water layer is with ETHYLE ACETATE (3 * 50mL) extractions.With the organic layer that merges through MgSO 4Drying is filtered and is concentrated, and (2-bromo-pyridin-4-yl)-(ES+m/z 226.48 for cyclopanecarboxaldehyde to obtain bullion 1-; 228.47), its not purified direct use.
With Textone (368mg; 3.26mmol) and biphosphate sodium-hydrate (449mg; 3.26mmol) drips of solution in 5mL water adds to bullion 1-(2-bromo-pyridin-4-yl)-cyclopanecarboxaldehyde (566mg; 2.50mmol) and the 2-methyl-2-butene (1.73mL, 16.3mmol) in the solution in the trimethyl carbinol (12mL), and at stirring at room gained reaction mixture.After 18 hours, this mixture is concentrated in a vacuum, use 1M HCl acidified aqueous solution to pH be 2, with salt solution (25mL) dilution, and with ETHYLE ACETATE (3 * 50mL) extract.With the organic layer that merges through Na 2SO 4Drying is filtered and is concentrated, and obtains bullion 1-(2-bromo-pyridin-4-yl)-cyclopropane-carboxylic acid, its not purified direct use.
In pressurized vessel, to bullion 1-(2-bromo-pyridin-4-yl)-cyclopropane-carboxylic acid (0.350g, 1.45mmol) add in the solution in the trimethyl carbinol (7mL) diphenyl phosphoryl azide (0.312mL, 1.45mmol) and triethylamine (0.202mL, 1.45mmol).Sealing should be managed and stirred these reaction mixtures at 90 ° of C.After 4 hours, this pressurized vessel cools off in ice bath, ventilates and opens.This reaction mixture is concentrated in a vacuum.The gained resistates is dissolved in the ETHYLE ACETATE (70mL), with ammonium chloride saturated aqueous solution (70mL) and saturated aqueous solution of sodium bicarbonate (70mL) washing, through MgSO 4Drying is filtered and is concentrated.Resistates is through the silica gel chromatography purifying, and the gradient elution with the 0-50% ETHYLE ACETATE in the heptane obtains [1-(2-bromo-pyridin-4-yl)-cyclopropyl]-t-butyl carbamate.
Room temperature to [1-(2-bromo-pyridin-4-yl)-the cyclopropyl]-t-butyl carbamate that stirs (0.160g, 0.511mmol) add in the solution in methylene dichloride (3mL) trifluoroacetic acid (1.0mL, 13mmol).After 18 hours, this reaction mixture is concentrated in a vacuum, obtain bullion title compound (ES+m/z213.49,215.40), it is an oily matter, its not purified direct use.
Synthesizing of embodiment 8:1-(2-bromo-pyridin-4-yl)-cyclobutyl amine trifluoroacetate (8)
Figure BDA00001782728400441
According to the cycloalkylation operation that is disclosed among the embodiment 7, use 1, the 3-dibromopropane replaces glycol dibromide, from (2-bromo-pyridin-4-yl)-acetonitrile (1.50g, 7.61mmol) preparation 1-(2-bromo-pyridin-4-yl)-tetramethylene formonitrile HCN.
According to the DIBAL-H operation that is disclosed among the embodiment 7, from 1-(2-bromo-pyridin-4-yl)-tetramethylene formonitrile HCN (1.26g, 5.20mmol) preparation 1-(2-bromo-pyridin-4-yl)-tetramethylene formaldehyde.
According to the oxidation operation that is disclosed among the embodiment 7, from 1-(2-bromo-pyridin-4-yl)-tetramethylene formaldehyde (532mg, 2.22mmol) preparation 1-(2-bromo-pyridin-4-yl)-cyclobutane formate (ES+m/z 256.40,258.38).
Ke Erdisi according to being disclosed among the embodiment 7 resets operation; Use the temperature of reaction of 100 ° of C; From 1-(2-bromo-pyridin-4-yl)-cyclobutane formate (0.100g, 0.390mmol) preparation [1-(2-bromo-pyridin-4-yl)-cyclobutyl]-t-butyl carbamate (ES+m/z 327.54,329.46).
According to disclosed Boc-deprotection operation among the embodiment 7, from [1-(2-bromo-pyridin-4-yl)-cyclobutyl]-t-butyl carbamate (82.0mg, 0.262mmol) preparation title compound (ES+m/z 227.30,229.27).
Synthesizing of embodiment 9:1-(5-methylsulfonyl-furans-2-yl)-cyclopropylamine hydrochloride (9)
Figure BDA00001782728400451
Coupling operation according to disclosed cupric iodide (I) among the embodiment 19-mediation; From [1-(5-iodo-furans-2-yl)-cyclopropyl]-t-butyl carbamate (0.500g, 1.43mmol) preparation [1-(5-methylsulfonyl-furans-2-yl)-cyclopropyl]-t-butyl carbamate; Yet, methane-sulfinic acid sodium is used as the coupling mating partner to replace 3-methoxyl group-3-oxo propane-1--sulfinic acid sodium.
In room temperature with [1-(5-methylsulfonyl-furans-2-yl)-cyclopropyl]-t-butyl carbamate (0.430g; 1.42mmol) be dissolved in two
Figure BDA00001782728400452
of 4M HClalkane solution (5.0mL, 20mmol).Stir after 16 hours, this mixture is evaporated under nitrogen gas stream.Gained oily solid is suspended in the ETHYLE ACETATE (5mL), adds ether (25mL), and filter this mixture, obtain the bullion title product, it is a solid, its not purified direct use.
Synthesizing of formula I compound
Synthesizing of embodiment 10:1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid [1-(5-methylsulfonyl-furans-2-yl)-cyclopropyl]-acid amides (10)
Figure BDA00001782728400453
To 1-(4-fluoro-the phenyl)-1H-pyrazolo [3 that stirs; 4-c] pyridine-4-formic acid (0.310g; 1.21mmol), N; N-diisopropylethylamine (0.630mL; 3.62mmol) and 1-(5-methylsulfonyl-furans-2-yl)-cyclopropylamine-hydrochloride (364mg, and 1.53mmol) adding in the mixture in DMF (30mL) (benzotriazole-1-base oxygen base) tripyrrole alkyl phosphorus
Figure BDA00001782728400454
hexafluorophosphate (PyBOP) (0.650g, 1.25mmol).After 18 hours, this mixture is diluted with ammonium chloride saturated aqueous solution (100mL), and with ETHYLE ACETATE (4 * 30mL) extractions.The organic layer that merges with brine wash (50mL), is used dried over sodium sulfate, filter and concentrate.Resistates is through the silica gel chromatography purifying, and the gradient elution with the 0-100% ETHYLE ACETATE in the hexane obtains title compound, and it is a solid.
Following compound uses disclosed couling process preparation among the embodiment 10; Yet, replace N with triethylamine, the N-diisopropylethylamine:
1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid [1-(5-bromo-pyrimidine-2-base)-cyclopropyl]-acid amides.
Synthesizing of embodiment 11:1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid [1-(2-bromo-pyridin-4-yl)-cyclopropyl]-acid amides (11)
Figure BDA00001782728400461
To 1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid (0.120g, 0.467mmol) add in the mixture in DMF (2mL) HATU (186mg, 0.490mmol).After 30 minutes, add N, the N-diisopropylethylamine (325 μ L, 1.87mmol) and 1-(2-bromo-pyridin-4-yl)-cyclopropylamine-trifluoroacetate (223mg, 0.507mmol), and this reaction mixture becomes homogeneous.After 18 hours, this mixture is concentrated in a vacuum, be dissolved in again in the ETHYLE ACETATE (50mL) also with (3 * 50mL) washings of 1N sodium hydroxide.Organic layer with ammonium chloride saturated aqueous solution (2 * 50mL), the washing of saturated aqueous solution of sodium bicarbonate (50mL), salt solution (50mL), through MgSO 4Drying is filtered in a vacuum and is concentrated.Resistates is through silica gel chromatography purifying twice, and the gradient elution with the 0-10% methyl alcohol in the methylene dichloride obtains title compound, and it is a solid.
Following compound uses disclosed couling process preparation among the embodiment 11;
1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid [1-(6-bromo-pyridin-3-yl)-cyclopropyl]-acid amides; With
1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid (1-pyridin-4-yl-cyclopropyl)-acid amides.
Synthesizing of embodiment 12:1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid (1-1,3,4-thiadiazoles-2-base-cyclopropyl)-acid amides (12)
Figure BDA00001782728400471
To 1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid (90.0mg 0.350mmol) adds N in the suspension in DMF (2mL), the N-diisopropylethylamine (243 μ L, 1.40mmol) and HBTU (159mg, 0.420mmol).After 20 minutes, add 1-1,3,4-thiadiazoles-2-base-cyclopropylamine (51.0mg, the 0.361mmol) solution in DMF (1mL), and with this mixture in stirred overnight at room temperature.This reaction mixture is poured in the saturated aqueous solution of sodium bicarbonate (50mL), adds ETHYLE ACETATE (30mL) and be separated.Water layer is used brine treatment, and with ETHYLE ACETATE (3 * 20mL) extractions.Concentrate the organic layer that is merged in a vacuum.This bullion thing is through the silica gel chromatography purifying, and the gradient elution with the 0-10% methyl alcohol in the methylene dichloride obtains title compound, and it is a solid.
Synthesizing of embodiment 13:1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid [1-(3-bromo-phenyl)-cyclopropyl]-acid amides (13)
Figure BDA00001782728400472
To 1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid (0.500g, 1.94mmol); 1-(3-bromophenyl) cyclopropylamine (453mg, 2.14mmol) and N, N-diisopropylethylamine (1.73mL; 9.72mmol) add in the solution in DMF (18mL) TBTU (0.780g, 2.43mmol).After 2 hours, this mixture is concentrated in a vacuum, is dissolved in ETHYLE ACETATE (200mL), and with 2N sodium hydroxide (3 * 100mL), ammonium chloride saturated aqueous solution (2 * 100mL), saturated aqueous solution of sodium bicarbonate (100mL), salt solution (100mL) wash.Organic layer is through MgSO 4Drying is filtered through silicagel pad, with ETHYLE ACETATE (3 * 100mL) wash-outs, and concentrated in a vacuum.Resistates is through the silica gel chromatography purifying, and the gradient elution with the 50-70% ETHYLE ACETATE in the heptane obtains solid, and this solid is ground with methylene dichloride, obtains title compound, and it is a solid.
Below compound use among the embodiment 13 disclosed couling process and prepare:
3-(1-{ [1-(4-fluoro-phenyl)-1c pyrazolo [3,4-c] pyridine-4-carbonyl]-amino }-cyclopropyl)-oil of Niobe;
1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid [1-(2-bromo-pyridin-4-yl)-cyclobutyl]-acid amides; With
1-(4-fluoro-phenyl)-1H-indazole-4-formic acid [1-(2-methylsulfonyl-pyridin-4-yl)-cyclopropyl]-acid amides.
Embodiment 14:3-(1-{ [1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-carbonyl]-amino }-cyclopropyl)-phenylformic acid (14) synthetic
Figure BDA00001782728400481
To 3-(1-{ [1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-carbonyl]-amino }-cyclopropyl)-(0.650g, 1.51mmol) (22.5mL adds LiOHH in the solution in mixture 3:1:1) to oil of Niobe in the THF/ methanol 2O (253mg, 6.04mmol).After 3 hours,, and concentrate in a vacuum with this reaction mixture of glacial acetic acid neutralization.Resistates is dissolved in 20% methanol solution (100mL) in the methylene dichloride.Add entry (100mL), and to use the 2M aqueous hydrochloric acid that this mixture is acidified to pH be 4.Separate each phase, and water layer is with (9 * 100mL) extractions of 20% methyl alcohol in the methylene dichloride.With the organic layer that merges through MgSO 4About 50mL is filtered and be concentrated into to drying.Filter gained crystalline solid, (3 * 2mL) washings and air-dry obtain title compound, and it is a solid with cold methanol.
Embodiment 15: [3-(1-{ [1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-carbonyl]-amino }-cyclopropyl)-benzoyl-amido]-methyl acetate (15) synthetic
Figure BDA00001782728400491
To 3-(1-{ [1-(4-fluoro-phenyl)-1H-pyrazolo [3; 4-c] pyridine-4-carbonyl]-amino }-cyclopropyl)-phenylformic acid (0.200g; 0.480mmol), Gly-OMe-HCl (68.1mg, 0.543mmol) and N, N-diisopropylethylamine (426 μ L; 2.40mmol) add in the solution in DMF (4.5mL) TBTU (192mg, 0.600mmol).After 4 hours, this mixture is concentrated in a vacuum.Resistates is dissolved in the ETHYLE ACETATE (100mL), and with 2N sodium hydroxide (3 * 50mL), ammonium chloride saturated aqueous solution (2 * 50mL), the washing of saturated aqueous solution of sodium bicarbonate (50mL), salt solution (50mL).Organic layer is through MgSO 4Drying is filtered and is concentrated.Resistates is through the silica gel chromatography purifying, and the gradient elution with the 0-8% methyl alcohol in the methylene dichloride obtains foam, and it grinds with ether (3mL), filters, and (3 * 3mL) washings and air-dry obtain title compound with cold ether.
Below compound use among the embodiment 15 disclosed couling process and prepare:
1-[3-(1-{ [1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-carbonyl]-amino }-cyclopropyl)-benzoyl-amido]-the cyclopropane-carboxylic acid methyl esters;
1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid { 1-[3-(cyano methyl-formamyl)-phenyl]-cyclopropyl }-acid amides; With
(S)-2-[3-(1-{ [1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-carbonyl]-amino }-cyclopropyl)-benzoyl-amido]-methyl propionate.
Synthesizing of embodiment 16:1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid [1-(3-formamyl-phenyl)-cyclopropyl]-acid amides (16)
Figure BDA00001782728400501
In the sealing load pipe; Stir 3-(1-{ [1-(4-fluoro-phenyl)-1H-pyrazolo [3 at 120 ° of C; 4-c] pyridine-4-carbonyl]-amino }-cyclopropyl)-(70.0mg is 0.163mmol) at the methanol solution of 7M ammonia (1.00mL, the solution in 7.00mmol) for oil of Niobe.After 78 hours, this reaction vessel is cooled to room temperature, ventilates and open.This reaction mixture is concentrated in a vacuum, and with the gained resistates through the silica gel chromatography purifying, the gradient elution with the 0-10% methyl alcohol in the methylene dichloride obtains the solid title compound.
Below compound use among the embodiment 16 disclosed method and prepare:
1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid { 1-[3-(carbamyl ylmethyl-formamyl)-phenyl]-cyclopropyl }-acid amides.
Synthesizing of embodiment 17:1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid [1-(3-methylamino formyl radical-phenyl)-cyclopropyl]-acid amides (17)
Figure BDA00001782728400502
In the sealing load pipe; Stir 3-(1-{ [1-(4-fluoro-phenyl)-1H-pyrazolo [3 at 90 ° of C; 4-c] pyridine-4-carbonyl]-amino }-cyclopropyl)-(70.0mg is 0.163mmol) at the methanol solution of 2M methylamine (3.0mL, the mixture in 6.0mmol) for oil of Niobe.After 18 hours, this reaction vessel is cooled to room temperature, ventilates and open.This reaction mixture is concentrated in a vacuum.Resistates is through the silica gel chromatography purifying, and the gradient elution with the 0-8% methyl alcohol in the methylene dichloride obtains title compound, and it is a solid.
Below compound use among the embodiment 17 disclosed method and prepare:
1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid { 1-[3-(methylamino formyl radical methyl-formamyl)-phenyl]-cyclopropyl }-acid amides.
Synthesizing of embodiment 18:1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid [1-(6-methylsulfonyl-pyridin-3-yl)-cyclopropyl]-acid amides (18)
With 1-(4-fluoro-phenyl)-1H-pyrazolo [3; 4-c] pyridine-4-formic acid [1-(6-bromo-pyridin-3-yl)-cyclopropyl]-acid amides (72.7mg; 0.161mmol), methane-sulfinic acid sodium (32.8mg; 0.321mmol) and cuprous iodide (I) (61.2mg, 0.321mmol) the solution exhaust in DMSO (1mL) and with argon purge three times, and heat at 130 ° of C.After 45 minutes, this reaction cooled to room temperature, and is added N, and N '-dimethyl-ethylenediamine (69 μ L, 0.64mmol).This mixture was stirred 30 minutes, dilute and stirred 15 minutes with ETHYLE ACETATE (20mL).Add ammonium chloride saturated aqueous solution (20mL); With gained mixture supersound process 30 minutes, and dilute with ETHYLE ACETATE (100mL).Separate each phase, and water layer is with ETHYLE ACETATE (3 * 20mL) extractions.With the organic layer that merges with ammonium chloride saturated aqueous solution (2 * 50mL), saturated aqueous solution of sodium bicarbonate (50mL), salt solution (50mL) wash, through MgSO 4Drying is filtered and is concentrated.Through the silica gel chromatography purifying, the gradient elution with the 0-8% methyl alcohol in the methylene dichloride obtains title compound with the gained resistates, and it is a solid.
Below compound use among the embodiment 18 disclosed method and prepare:
1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid [1-(2-methylsulfonyl-pyridin-4-yl)-cyclopropyl]-acid amides;
1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid [1-(5-methylsulfonyl-pyrimidine-2-base)-cyclopropyl]-acid amides;
1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid [1-(3-methylsulfonyl-phenyl)-cyclopropyl]-acid amides; With
1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid [1-(2-methylsulfonyl-pyridin-4-yl)-cyclobutyl]-acid amides.
Embodiment 19:3-[5-(1-{ [1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-carbonyl]-amino }-cyclopropyl)-pyridine-2-sulfuryl base]-methyl propionate (19) synthetic
With 1-(4-fluoro-phenyl)-1H-pyrazolo [3; 4-c] pyridine-4-formic acid [1-(6-bromo-pyridin-3-yl)-cyclopropyl]-acid amides (0.250g; 0.553mmol), 3-methoxyl group-3-oxo propane-1--sulfinic acid sodium (289mg, 1.66mmol) and cuprous iodide (I) (316mg, 1.66mmol) solution in DMSO (2mL) places microwave tube; Exhaust, and with argon purge three times.At 110 ° of C with this reaction mixture microwave heating 2 hours, with ETHYLE ACETATE (200mL) dilution, with ammonium chloride saturated aqueous solution (4 * 100mL), saturated aqueous solution of sodium bicarbonate (100mL), salt solution (100mL) wash, through MgSO 4Drying is filtered and is concentrated.Through the silica gel chromatography purifying, the gradient elution with the 50-100% ETHYLE ACETATE in the heptane obtains title compound with the gained resistates, and it is a solid.
Following compound uses disclosed method preparation among the embodiment 19:
3-[3-(1-{ [1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-carbonyl]-amino }-cyclopropyl)-benzenesulfonyl]-methyl propionate.
Synthesizing of embodiment 20:1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid [1-(6-amino-sulfonyl-pyridin-3-yl)-cyclopropyl]-acid amides (20)
To the 3-[5-(1-{ [1-(4-fluoro-phenyl)-1H-pyrazolo [3 that stirs; 4-c] pyridine-4-carbonyl]-amino }-cyclopropyl)-the pyridine-2-sulfuryl base]-methyl propionate (153mg; 0.292mmol) add in the solution in DMSO (4mL) freshly prepared 15% sodium methylate methanol solution (0.110mL, 0.306mmol).After 15 minutes, this mixture is placed water-bath, and add the N-hydroxylamine-o-sulfonic acid (661mg, 5.84mmol) and sodium acetate (384mg, 4.68mmol) solution in water (16mL).Remove water-bath, and with this reaction mixture in stirring at room.After 60 hours, this mixture is diluted with ETHYLE ACETATE (20mL) and water (20mL).Separate each phase, and water layer is with ETHYLE ACETATE (3 * 20mL) extractions.With the pH regulator to 7 of 10% sodium bicarbonate aqueous solution with the organic layer that is merged.(3 * 20mL) washings are through MgSO for the organic layer water 4Drying is filtered and is concentrated.Resistates is used 100% eluent ethyl acetate through the silica gel chromatography purifying.The gained solid grinds (3 times) with ether, and filtration is also dry under vacuum, obtains title compound, and it is a solid.
Below compound use among the embodiment 20 disclosed method and prepare:
1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid [1-(3-amino-sulfonyl-phenyl)-cyclopropyl]-acid amides.
Synthesizing of embodiment 21:1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid [1-(6-methylamino-pyridin-3-yl)-cyclopropyl]-acid amides (21)
Figure BDA00001782728400541
160 ° of C heating 1-(4-fluoro-phenyl)-1H-pyrazolo [3 is housed; 4-c] pyridine-4-formic acid [1-(6-bromo-pyridin-3-yl)-cyclopropyl]-acid amides (0.200g; 0.442mmol), ethanolic soln (0.250mL, 1.99mmol) pressure tube of the mixture in N-NMF (1mL) of 33% methylamine.After 36 hours, with this reaction cooled to room temperature, and with the dilution of ETHYLE ACETATE (20mL) and water (20mL).Separate each phase, and water layer is with ETHYLE ACETATE (3 * 20mL) extractions.With the organic layer that merges with ammonium chloride saturated aqueous solution (3 * 100mL), saturated aqueous solution of sodium bicarbonate (100mL), salt solution (100mL) wash, through MgSO 4Drying is filtered and is concentrated.Resistates is through the silica gel chromatography purifying, and the 0-15% methanol-eluted fractions with in the methylene dichloride obtains title compound, and it is a solid.
Synthesizing of embodiment 22:1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid [1-(6-morpholine-4-base-pyridin-3-yl)-cyclopropyl]-acid amides (22)
Figure BDA00001782728400542
In pressure tube, 160 ° of C heating 1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid [1-(6-bromo-pyridin-3-yl)-cyclopropyl]-acid amides (35mg, 0.077mmol) and morpholine (68 μ L, 0.77mmol) solution in DMSO (1mL).After 40 hours, this mixture is cooled to room temperature, with EtOAc (50mL) dilution, and with ammonium chloride saturated aqueous solution (2 * 50mL), saturated aqueous solution of sodium bicarbonate (50mL), salt solution (50mL) wash, through MgSO 4Drying is filtered and is concentrated.The gained solid is through the silica gel chromatography purifying, and the gradient elution with the 0-5% methyl alcohol in the methylene dichloride obtains solid, and this solid grinds with ether (5mL), filters and drying, obtains title compound.
Synthesizing of embodiment 23:1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid [1-(3-trifluoromethyl-phenyl)-cyclopropyl]-acid amides (23)
To 1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid (40.0mg, 0.156mmol) drip in the suspension in methylene dichloride (1mL) oxalyl chloride (14 μ L, 0.16mmol).After 10 minutes, add a N, dinethylformamide, and at this suspension of stirring at room.After 60 minutes, (14 μ L 0.16mmol), and add a N, dinethylformamide to add another part oxalyl chloride.Stir after 30 minutes, remove in a vacuum and desolvate; Be suspended in the methylene dichloride (1mL) resistates also concentrated in a vacuum.With resistates under vacuum dry 30 minutes; Be suspended in the methylene dichloride (1mL), and with its add 1-(3-trifluoromethyl-phenyl)-cyclopropylamine hydrochloride (74.1mg, 0.312mmol) and N; (0.080mL is 0.46mmol) in the solution in methylene dichloride (500 μ L) for the N-diisopropylethylamine., also concentrate after 15 hours in the room temperature jolting with methyl alcohol (500 μ L) termination reaction.Resistates through the reversed-phase HPLC purifying, is used the gradient elution of Water BEH post (2.1 * 50mm C181.7 μ M) and the 10-95% acetonitrile in the water that contains 0.05% formic acid, obtain title compound.
Below compound use among the embodiment 23 disclosed method and prepare:
1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid [1-(3-methoxyl group-phenyl)-cyclopropyl]-acid amides;
1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid [1-(6-dimethylamino-pyridine-2-yl)-cyclopropyl]-acid amides;
1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid (1-pyridin-3-yl-cyclopropyl)-acid amides;
1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid [1-(4-methoxyl group-phenyl)-cyclopropyl]-acid amides;
1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid [1-(4-fluoro-phenyl)-cyclopropyl]-acid amides;
1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid (tolyl-cyclopropyl between 1-)-acid amides;
1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid [1-(3-chloro-phenyl)-cyclopropyl]-acid amides;
4-(1-{ [1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-carbonyl]-amino }-cyclopropyl)-phenylformic acid;
1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid [1-(3-fluoro-phenyl)-cyclopropyl]-acid amides;
1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid [1-(4-chloro-phenyl)-cyclopropyl]-acid amides;
1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid (1-p-methylphenyl-cyclopropyl)-acid amides;
1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid (1-phenyl-cyclopropyl)-acid amides;
1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid (1-o-tolyl-cyclopropyl)-acid amides;
1-(4-fluoro-phenyl)-1H-pyrazolo [3; 4-c] pyridine-4-formic acid [1-(3-cyclopropyl-1; 2,4- diazole-5-yl)-cyclopropyl]-acid amides;
1-(4-fluoro-phenyl)-1H-pyrazolo [3; 4-c] pyridine-4-formic acid [1-(5-cyclopropyl-1; 2,4- diazole-3-yl)-cyclopropyl]-acid amides;
1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid [1-(2-methyl-thiazole-4-yl)-cyclopropyl]-acid amides;
[2-(1-{ [1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-carbonyl]-amino }-cyclopropyl)-the pyridin-4-yl methyl]-t-butyl carbamate;
1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid [1-(4-methoxyl group-pyridine-2-yl)-cyclopropyl]-acid amides;
1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid [1-(4-chloro-pyridine-2-yl)-cyclopropyl]-acid amides;
1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid [1-(5-bromo-pyridine-2-yl)-cyclopropyl]-acid amides;
1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid [1-(4-iodo-pyridine-2-yl)-cyclopropyl]-acid amides;
1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid [1-(4-bromo-phenyl)-cyclopropyl]-acid amides;
[6-(1-{ [1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-carbonyl]-amino }-cyclopropyl)-the pyridin-3-yl methyl]-t-butyl carbamate;
1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid [1-(4-methoxyl group-phenyl)-cyclobutyl]-acid amides; With
1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid [1-(4-fluoro-phenyl)-cyclobutyl]-acid amides.
Below compound use disclosed couling process among the embodiment 23, then use and carry out the Boc-deprotection according to disclosed method among the embodiment 7 and prepare:
1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid [1-(4-amino methyl-pyridine-2-yl)-cyclopropyl]-acid amides; With
1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid [1-(5-amino methyl-pyridine-2-yl)-cyclopropyl]-acid amides.
Synthesizing of embodiment 24:1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid { 1-[6-(ethanoyl-methyl-amino)-pyridin-3-yl]-cyclopropyl }-acid amides (24)
Figure BDA00001782728400571
(40mg, 0.099mmol) heating of the solution in diacetyl oxide (1mL) is 16 hours with 1-(4-fluoro-phenyl)-1H-pyrazolo [3,4-c] pyridine-4-formic acid [1-(6-methylamino-pyridin-3-yl)-cyclopropyl]-acid amides at 60 ° of C.This solution is cooled to room temperature,, stirred 20 minutes, and extract with ETHYLE ACETATE (5mL) with the 1N NaOH aqueous solution dilution of 3mL.Organic layer filters and concentrates through dried over mgso.Resistates is through the silica gel chromatography purifying, and the gradient elution with the 0-10% methyl alcohol in the methylene dichloride obtains title compound.
Synthesizing of embodiment 25:6-bromo-1-(4-fluoro-phenyl)-1H-indazole-4-formic acid [1-(2-methylsulfonyl-pyridin-4-yl)-cyclopropyl]-acid amides (25a) and 1-(4-fluoro-phenyl)-6-iodo-1H-indazole-4-formic acid [1-(2-methylsulfonyl-pyridin-4-yl)-cyclopropyl]-acid amides (25b)
Cross coupling operation according to disclosed copper-mediated among the embodiment 2; From 6-bromo-1H-indazole-4-methyl-formiate (10.0g, 39.2mmol) mixture of preparation 6-bromo-1-(4-fluoro-phenyl)-1H-indazole-4-methyl-formiate and 1-(4-fluoro-phenyl)-6-iodo-1H-indazole-4-methyl-formiate.
In the solution of mixture (500mg) in THF (12mL), methyl alcohol (4mL) and water (4mL) of 6-bromo-1-(4-fluoro-phenyl)-1H-indazole-4-methyl-formiate and 1-(4-fluoro-phenyl)-6-iodo-1H-indazole-4-methyl-formiate, add LiOHH 2O (240mg, 5.73mmol).,, concentrate, and dilute after 4 hours in stirring at room with 20% methanol solution (100mL) in the methylene dichloride with this reaction mixture of 1M HCl neutralization.Add entry (100mL), and with the pH regulator to 4 of 1M HCl with this mixture.Separate each phase, and water layer is with (9 * 100mL) extractions of 20% methanol solution in the methylene dichloride.The organic layer that merges through dried over mgso, is filtered and concentrates, obtain the mixture of 6-bromo-1-(4-fluoro-phenyl)-1H-indazole-4-formic acid and 1-(4-fluoro-phenyl)-6-iodo-1H-indazole-4-formic acid, it is a solid.
According to disclosed coupling operation among the embodiment 13; Use the mixture (420mg) and 1-(2-methylsulfonyl-pyridin-4-yl)-cyclopropylamine trifluoroacetate (851mg of 6-bromo-1-(4-fluoro-phenyl)-1H-indazole-4-formic acid and 1-(4-fluoro-phenyl)-6-iodo-1H-indazole-4-formic acid; 1.93mmol) prepare title compound, and use the gradient purifying of C18 post and the acetonitrile in the water that contains 0.1% trifluoroacetic acid through reversed-phase HPLC.According to the coupling operation of disclosed copper-mediated among the WO 2009/134666 (embodiment 7), then through above-mentioned Boc deprotection operation (embodiment 3), prepare midbody 1-(2-methylsulfonyl-pyridin-4-yl)-cyclopropylamine trifluoroacetate from [1-(2-bromo-pyridin-4-yl)-cyclopropyl]-t-butyl carbamate.
Synthesizing of embodiment 26:1-(4-fluoro-phenyl)-6-methylsulfonyl-1H-indazole-4-formic acid [1-(2-methylsulfonyl-pyridin-4-yl)-cyclopropyl]-acid amides (26)
According to disclosed coupling operation among the embodiment 18, from mixture (100mg) synthesising title compound of 6-bromo-1-(4-fluoro-phenyl)-1H-indazole-4-formic acid [1-(2-methylsulfonyl-pyridin-4-yl)-cyclopropyl]-acid amides and 1-(4-fluoro-phenyl)-6-iodo-1H-indazole-4-formic acid [1-(2-methylsulfonyl-pyridin-4-yl)-cyclopropyl]-acid amides.
Synthesizing of embodiment 27:6-cyanic acid-1-(4-fluoro-phenyl)-1H-indazole-4-formic acid [1-(2-methylsulfonyl-pyridin-4-yl)-cyclopropyl]-acid amides (27)
Figure BDA00001782728400601
To 6-bromo-1-(4-fluoro-phenyl)-1H-indazole-4-formic acid [1-(2-methylsulfonyl-pyridin-4-yl)-the cyclopropyl]-acid amides that stirs and 1-(4-fluoro-phenyl)-6-iodo-1H-indazole-4-formic acid [1-(2-methylsulfonyl-pyridin-4-yl)-cyclopropyl]-acid amides (150mg) at DMF (1.0mL; The degassing and anhydrous) adds tetrakis triphenylphosphine palladium (33mg in the solution in; 0.028mmol) and zinc cyanide (40mg, 0.34mmol).With this solution exhaust and with argon purge (3 times), and be warmed to 120 ° of C.After 3 hours, this reaction cooled to room temperature, is diluted with ammonium chloride saturated aqueous solution (50mL), and with ETHYLE ACETATE (3 * 50mL) extractions.The organic layer that merges with brine wash (50mL), through dried over mgso, is filtered and concentrates.With resistates through SiO 2Purifying, the gradient elution of the 50-100% ETHYLE ACETATE in the use heptane obtains solid, and this solid grinds with ether, obtains title product.
The assessment of biological property
During the functional cell of calcium flux is measured in measuring the CCR1 transfectional cell, assessed the interactional ability of compounds block CCR1 and MIP-1 α.
Stably the non-adherent cell (HTS005C) of express recombinant CCR1 and G-α-16 (available from Chemicon company) is grown in the RPMI1640 substratum (Mediatech 10-080-CM) that replenishes 10%FBS, 0.4mg/mL Geneticin and penicillin/streptomycin.Measuring the same day,,, in cell, use calcium 4 dyestuffs (Molecular Devices R7448) with probenecid (InvitrogenP346400), load 1 hour with 8E5 cell/mL in room temperature.After 1 hour, it under the density of 20,000 cells/well, is seeded in the plate of 384-aperture tissue culture treated.The testing compound of dilution is compatibly added in the hand-hole, and reaching maximum concentration is 3,000nM (with 4 times of 10 kinds of dose dilution altogether).The ultimate density of DMSO is 1%.Buffer reagent is for having 20mM HEPES, the HBSS under pH 7.4 (Invitrogen 14025).Cell was cultivated 30 minutes at 37 ℃, then incubated at room temperature 30 minutes.Plate is transferred to HAMAMATSUFDSS6000, wherein under the EC80 ultimate density, adds the MIP-1 α among the 1%BSA.All plates must load reading in 4 hours that begin at dyestuff.To contain the hole of DMSO but not the compound of dilution+/-MIP-1 α is as contrast.Data are used Acticity Base software analysis.
Generally speaking, in said determination, the preferred effect of compound (potency) scope (IC 50) between 0.1nM to 3 μ M, and most preferred effect scope is 0.1nM to 50nM.
Representative compound of the present invention is tested in said determination, and has demonstrated the activity as the CCR1 antagonist, and this has represented another embodiment of the invention.
Table II
Figure BDA00001782728400611
Figure BDA00001782728400621
Figure BDA00001782728400631
Figure BDA00001782728400641
Figure BDA00001782728400651
Method of use
The compounds of this invention is effective antagonist of CCR1 and its chemokine ligand interphase interaction, and therefore suppresses the activity of CCR1-mediation.Therefore, in an embodiment of the invention, the method for using The compounds of this invention treatment autoimmune conditions is provided.In another embodiment, the method for using The compounds of this invention treatment inflammatory conditions is provided.
Do not hope to be subject to theory; Through the interaction between antagonism CCR1 and its chemokine ligand; This compounds block is urged inflammation (pro-inflammatory) cell and (is comprised monocyte, scavenger cell, dendritic cell, oxyphie and T cell (TH1); And other CCR1 positive cell) to the chemotaxis of Inflamed tissue, therefore improves the chronic inflammatory diseases relevant with autoimmune disorder.Therefore; The active inhibition of CCR1 is a kind of prevention and the meaningful mode of treatment various autoimmune venereal disease disease, and said illness comprises that inflammatory diseases, autoimmune disorder, organ people (2001) JBC 276 such as (the 4199th page) Horuk and marrow graft rejection and other and short inflammatory cell are interior and flows relevant illness.For example; The compounds of this invention can be used for prevention or treat acute or chronic inflammatory diseases, transformation reactions, contact dermatitis, psoriasis, rheumatoid arthritis, multiple sclerosis, type i diabetes, inflammatory bowel, Guillain-Barre syndrome, Crohn disease, ulcerative colitis, graft versus host disease (and other form of organ or marrow graft rejection), Alzheimer people (2003) Ann Neurol 54 such as (the 638th page) Halks-Miller, asthma people (2008) J.Immun 180 such as (the 1268th page) Jouber, chronic nephropathy people (1999) J.Clin.Invest.104 such as (the 1549th page) Topham, Sepsis people (2007) Am J.Physio 292 G1173 pages or leaves such as () He, autoimmune myocarditis people (2006) J Mol Cell Cardiology 40 such as (the 853rd page) Futamats, (Blood (2001) 97 for multiple myeloma; The 3349-3353 page or leaf), COPD (Expert Opin.Investig.Drugs (2005) 14, the 785-796 page or leaf) and systemic lupus erythematous.Particularly, this compound can be used for prevention or treatment rheumatoid arthritis and multiple sclerosis.Other illness relevant with the transportation of short inflammatory cell is understood by those skilled in the art, and can also use compound of the present invention and combination treatment.
For the treatment of above-mentioned disease and symptom, effective dose is usually in the about 0.01mg/ kilogram of every dosage The compounds of this invention to the scope of about 100mg/ kg body weight in the treatment; The about 0.1mg/ kilogram of preferred every dosage to about 20mg/ kg body weight.For example, for the patient who gives 70 kilograms, dosage range is extremely about 7000mg of the about 0.7mg of every dosage The compounds of this invention, and the about 7.0mg of preferred every dosage is to about 1400mg.Possibly need routine dose optimization to a certain degree, with the most suitable dosage of decision and mode.Active ingredient can give 1 to 6 time in one day.
General administration and pharmaceutical composition
When as drug use, the The compounds of this invention typical case gives with the form of pharmaceutical composition.The operation that said composition can be used in the field of medicaments and known prepares, and comprises at least a compound of the present invention.The compounds of this invention is auxiliary agent administration alone or in combination also; This auxiliary agent strengthens the stability of The compounds of this invention, promotes to contain the pharmaceutical composition administration in some embodiments of auxiliary agent, and the dissolving or the dispersion of increase are provided; Increase antagonistic activity, adjunctive therapy etc. is provided.Compound of the present invention other active substance of the present invention that can use separately or arrange in pairs or groups, the material of optional other tool pharmacological activity of also arranging in pairs or groups.Generally speaking, The compounds of this invention with treat or pharmaceutically significant quantity give, but can give with low amount for diagnosis or other purpose.
The compounds of this invention with purified form or in suitable administered in pharmaceutical compositions, can make any administration model of accepting of pharmaceutical composition carry out.Therefore; Administration for example can be with oral way, contains clothes mode (for example hypogloeeis mode), intranasal mode, parenteral mode, local mode, through skin mode, vagina mode or rectal; Be solid, semisolid, through lyophilized powder or liquid dosage form form; For example tablet, suppository, pill, soft elasticity and hard gelatin capsule, powder, solution, suspension-s or aerosol etc. preferably are the unit dosage of the simple administration that is fit to correct dose.Pharmaceutical composition generally comprise conventional medical carrier or vehicle and as should/a kind of The compounds of this invention of promoting agent, and can comprise other medicinal agent, medicine, carrier, auxiliary agent, thinner, mediator or its combination in addition.This pharmaceutically acceptable vehicle, carrier or additive, and preparation is well known to those skilled in the art about the method for the pharmaceutical composition of various models or administration.The current state of this area is Remington:The Science and Practice of Pharmacy for example, and the 20th edition, A.Gennaro (volume), Lippincott Williams & Wilkins, 2000; Handbook of Pharmaceutical Additives, Michael and Irene Ash (volume), Gower, 1995; Handbook of Pharmaceutical Excipients, A.H.Kibbe (volume), American Pharmaceutical Ass ' n, 2000; H.C.Ansel and N.G.Popovish, Pharmaceutical Dosage Forms and Drug Delivery Systerms, the 5th edition, Lea and Febiger, 1990; Every piece is hereby incorporated by, so that the current state of this area to be described better.
Expect that as those skilled in the art with the form that is chosen in The compounds of this invention used in the specific medication preparation (for example salt), it has becomes the needed suitable physical features of effective preparation (for example water solubility).

Claims (20)

1. formula (I) compound or its pharmacy acceptable salt
Figure FDA00001782728300011
Wherein
X is nitrogen or C-R 2
Ar 1Be carbocyclic ring, heteroaryl or heterocyclic radical, it is respectively randomly by one to three R aReplace;
Ar 2Be carbocyclic ring, heteroaryl or heterocyclic radical, it is respectively randomly by one to three R bReplace;
Ring G is carbocyclic ring or heterocyclic radical, and it is respectively randomly by one or two R gReplace;
R 1Be hydrogen, C 1-6Alkyl or C 1-6Alkoxy C 1-6Alkyl;
R 2Be hydrogen or R a
R aBe C 1-6Alkyl, C 3-10Naphthenic base, C 1-6Alkoxyl group, C 1-6Alkylthio, C 1-6Alkyl sulphonyl, C 1-6Alkoxy carbonyl, amino, list-or two-C 1-6Alkylamino, C 3-6Cycloalkyl amino, C 1-6Alkyl amino-carbonyl, C 1-6Acyl group, C 1-6Acyl amino, C 1-6Dialkyl amino carbonyl, hydroxyl, halogen, cyanic acid, nitro, oxo, R 3-S (O) m-NH-, R 3-NH-S (O) m-, aryl or carboxyl;
R bFor hydroxyl, carboxyl, halogen ,-(CH 2) n-CN ,-(CH 2) n-CO 2C 1-6Alkyl, nitro ,-SO 3H, C 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl, C 3-10Naphthenic base, C 1-6Alkoxyl group, C 1-6Alkyl C (O)-,-(CH 2) n-NR cR d, R 3-S (O) m(CH 2) 0-1-, R 3-S (O) m-NR e-, R 3-NR e-S (O) m(CH 2) 0-1-,-NR f-C (O)-R e,-(CH 2) y-C (O)-(CH 2) n-NR cR d, heterocyclic radical, aryl or heteroaryl, each R bUnder possible situation randomly by halogenation or by 1 to 3 C 1-6Alkyl, hydroxyl, C 1-6Acyl group, C 1-6Alkoxy carbonyl, C 1-6Alkyl-S (O) m-, aryl or carboxyl substituted;
Each R c, R dBe hydrogen, C independently 1-6Alkyl, C 1-6Acyl group, C 3-10Naphthenic base, C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, cyanic acid-C 1-6Alkyl, C 1-6Alkyl C 1-6Alkoxyl group, C 1-6Alkyl sulphonyl, C 1-6Alkoxy carbonyl C 0-3Alkyl, C 1-6Alkoxy carbonyl C 3-10Naphthenic base ,-(CH 2) n-C (O)-NR eR fOr-(CH 2) n-NR eR f
Each R e, R fBe hydrogen, C independently 1-6Alkyl, C 3-10Naphthenic base, C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, list-or two-C 1-6Alkylamino C 1-6Alkyl, hydroxyl C 1-6Alkyl or C 1-6Acyl group;
R gBe C 1-6Alkyl, wherein said C 1-6Alkyl is randomly by partially or completely halogenation, C 2-6Thiazolinyl, carbocyclic ring, C 1-6Alkoxyl group, carbocylic radical-C 1-6Alkoxyl group, carbocylic radical-C 1-6Alkyl, hydroxyl C 1-6Alkyl, hydroxyl ,-(CH 2) n-CO 2C 1-6Alkyl or oxo;
R 3Be hydrogen, C 1-6Alkyl, C 3-6Naphthenic base, heterocyclic radical (CH 2) 0-1, single-or two-C 1-6Alkylamino, list-or two-C 1-6Alkylamino (CH 2) 2-3N (R e)-, aryl or heteroaryl, its each randomly by 1 to 3 C 1-6Alkyl, C 3-6Naphthenic base, C 1-6Alkoxyl group, halogen, hydroxyl, oxo, carboxyl ,-C (O) NR eR f, amino, single-or two-C 1-6Alkylamino, C 1-6Alkoxy carbonyl or C 1-6Acyl amino replaces;
Each n, y are 0-3 independently;
Each m is 0-2 independently.
2. the compound of claim 1 or its pharmacy acceptable salt, and wherein
Ring G is for randomly by one or two R gSubstituted carbocyclic ring.
3. the compound of claim 2 or its pharmacy acceptable salt, and wherein
X is a nitrogen;
Ar 1For randomly by one to three R aSubstituted carbocyclic ring;
Ar 2Be carbocyclic ring or heteroaryl, it is respectively randomly by one to three R bReplace;
R 1Be hydrogen;
R aBe C 1-3Alkyl, C 1-3Alkoxyl group, two-C 1-6Alkylamino, methyl sulphonyl, halogen or cyanic acid;
R bFor hydroxyl, carboxyl, halogen ,-(CH 2) n-CN ,-(CH 2) n-CO 2C 1-6Alkyl, nitro ,-SO 3H, C 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl, C 3-10Naphthenic base, C 1-6Alkoxyl group, C 1-6Alkyl C (O)-,-(CH 2) n-NR cR d, R 3-S (O) m(CH 2) 0-1-, R 3-S (O) m-NR e-, R 3-NR e-S (O) m(CH 2) 0-1-,-NR f-C (O)-R e,-(CH 2) y-C (O)-(CH 2) n-NR cR d, heterocyclic radical, aryl or heteroaryl, each R bUnder possible situation randomly by halogenation or by 1 to 3 C 1-6Alkyl, C 1-6Acyl group, C 1-6Alkoxy carbonyl, C 1-6Alkyl-S (O) m-, aryl or carboxyl substituted;
R 3Be hydrogen, C 1-6Alkyl, C 3-6Naphthenic base, heterocyclic radical (CH 2) 0-1, single-or two-C 1-6Alkylamino, list-or two-C 1-6Alkylamino (CH 2) 2-3N (C 1-6Alkyl)-, aryl or heteroaryl, its each randomly by 1 to 2 C 1-6Alkyl, C 3-6Naphthenic base, C 1-6Alkoxyl group, halogen, hydroxyl, oxo, carboxyl ,-C (O) NR eR f, amino, single-or two-C 1-6Alkylamino, C 1-6Alkoxy carbonyl or C 1-6Acyl amino replaces.
4. the compound of claim 3 or its pharmacy acceptable salt, and wherein
Ar 1For by one or two R aSubstituted phenyl;
Ar 2For phenyl, thiadiazolyl group,
Figure FDA00001782728300031
Di azoly, pyrimidyl, furyl, thiazolyl or pyridyl, it is respectively randomly by one or two R bReplace;
Ring G is cyclopropyl or cyclobutyl;
R aBe halogen;
R bFor hydroxyl, carboxyl, halogen ,-CF 3,-CN ,-SO 3H, C 1-3Alkyl, C 3-6Naphthenic base C 1-3Alkoxyl group ,-(CH 2) n-CO 2C 1-3Alkyl ,-(CH 2) n-NR cR d, R 3-S (O) m(CH 2) 0-1-, R 3-S (O) 2-NR e-, R 3-NR e-S (O) 2(CH 2) 0-1-,-NR f-C (O)-R e,-(CH 2) y-C (O)-NR cR dOr morpholinyl;
Each R c, R dBe hydrogen, C independently 1-3Alkyl, C 1-3Acyl group, cyanic acid-C 1-3Alkyl, C 1-3Alkoxy carbonyl C 0-3Alkyl, C 1-3Alkoxy carbonyl C 3-6Naphthenic base or-(CH 2) n-C (O)-NR eR f
Each R e, R fBe hydrogen or C independently 1-3Alkyl;
R 3Be hydrogen or C 1-6Alkyl, it is respectively randomly by one or two C 1-6Alkoxyl group or oxo replace.
5. the compound of claim 4 or its pharmacy acceptable salt, and wherein
Ring G is a cyclopropyl;
R aFor-F or-Cl;
R bFor-CH 3, carboxyl ,-F ,-Cl ,-Br ,-I ,-CF 3, cyclopropyl ,-OCH 3,-CO 2Me ,-NR cR d,-CH 2-NR cR d, R 3-S (O) m-, R 3-S (O) 2-NR e-, R 3-NR e-S (O) 2-,-NR f-C (O)-R e,-C (O) NR cR dOr morpholinyl;
Each R c, R dBe independently hydrogen ,-CH 3,-C (O) CH 3,-CH 2CN, C 1-4Alkoxy carbonyl, methoxycarbonyl-C 1-2Alkyl-, methoxycarbonyl-C 3Naphthenic base-or-(CH 2)-C (O)-NR eR f
Each R e, R fBe independently hydrogen or-CH 3
R 3Be hydrogen or C 1-4Alkyl, its each randomly by one or two-OCH 3Or oxo replaces.
6. the compound of claim 5 or its pharmacy acceptable salt, and wherein
X is C-R 2
Ar 1For randomly by one to three R aSubstituted carbocyclic ring;
Ar 2Be carbocyclic ring or heteroaryl, it is respectively randomly by one to three R bReplace;
Ring G is for randomly by one or two R gSubstituted carbocyclic ring;
R 1Be hydrogen;
R 2Be hydrogen or R a
R aBe C 1-3Alkyl, C 1-3Alkoxyl group, two-C 1-6Alkylamino, methyl sulphonyl, halogen or cyanic acid;
R bFor hydroxyl, carboxyl, halogen ,-(CH 2) n-CN ,-(CH 2) n-CO 2C 1-6Alkyl, nitro ,-SO 3H, C 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl, C 3-10Naphthenic base, C 1-6Alkoxyl group, C 1-6Alkyl C (O)-,-(CH 2) n-NR cR d, R 3-S (O) m(CH 2) 0-1-, R 3-S (O) m-NR e-, R 3-NR e-S (O) m(CH 2) 0-1-,-NR f-C (O)-R e,-(CH 2) y-C (O)-(CH 2) n-NR cR d, heterocyclic radical, aryl or heteroaryl, each R bUnder possible situation randomly by halogenation or by 1 to 3 C 1-6Alkyl, C 1-6Acyl group, C 1-6Alkoxy carbonyl, C 1-6Alkyl-S (O) m-, aryl or carboxyl substituted;
Each R c, R dBe hydrogen, C independently 1-6Alkyl, C 1-6Acyl group, C 3-10Naphthenic base, C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, cyanic acid C 1-6Alkyl, C 1-6Alkyl C 1-6Alkoxyl group, C 1-6Alkyl sulphonyl, C 1-6Alkoxy carbonyl C 0-3Alkyl, C 1-6Alkoxy carbonyl C 3-10Naphthenic base ,-(CH 2) n-C (O)-NR eR fOr-(CH 2) n-NR eR f
Each R e, R fBe hydrogen, C independently 1-6Alkyl, C 3-10Naphthenic base, C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, list-or two-C 1-6Alkylamino C 1-6Alkyl, hydroxyl C 1-6Alkyl or C 1-6Acyl group;
R 3Be hydrogen, C 1-6Alkyl, C 3-6Naphthenic base, heterocyclic radical (CH 2) 0-1, single-or two-C 1-6Alkylamino, list-or two-C 1-6Alkylamino (CH 2) 2-3N (C 1-6Alkyl)-, aryl or heteroaryl, its each randomly by 1 to 2 C 1-6Alkyl, C 3-6Naphthenic base, C 1-6Alkoxyl group, halogen, hydroxyl, oxo, carboxyl ,-C (O) NR eR f, amino, single-or two-C 1-6Alkylamino, C 1-6Alkoxy carbonyl or C 1-6Acyl amino replaces.
7. the compound of claim 6 or its pharmacy acceptable salt, and wherein
Ar 1For by one or two R aSubstituted phenyl;
Ar 2For phenyl, thiadiazolyl group,
Figure FDA00001782728300041
Di azoly, pyrimidyl, furyl, thiazolyl or pyridyl, its each randomly by one or two R bReplace;
Ring G is cyclopropyl or cyclobutyl;
R aBe C 1-3Alkyl, methyl sulphonyl, halogen or cyanic acid;
R bFor hydroxyl, carboxyl, halogen ,-CF 3,-CN ,-SO 3H, C 1-3Alkyl, C 3-6Naphthenic base C 1-3Alkoxyl group ,-(CH 2) n-CO 2C 1-3Alkyl ,-(CH 2) n-NR cR d, R 3-S (O) m(CH 2) 0-1-, R 3-S (O) 2-NR e-, R 3-NR e-S (O) 2(CH 2) 0-1-,-NR f-C (O)-R e,-(CH 2) y-C (O)-NR cR dOr morpholinyl;
Each R c, R dBe hydrogen, C independently 1-3Alkyl, C 1-3Acyl group, cyanic acid-C 1-3Alkyl, C 1-3Alkoxy carbonyl C 0-3Alkyl, C 1-3Alkoxy carbonyl C 3-6Naphthenic base or-(CH 2) n-C (O)-NR eR f
Each R e, R fBe hydrogen or C independently 1-3Alkyl;
R 3Be hydrogen or C 1-6Alkyl, it is respectively randomly by one or two C 1-6Alkoxyl group or oxo replace.
8. the compound of claim 7 or its pharmacy acceptable salt, and wherein
Ring G is a cyclopropyl;
R aFor-F or-Cl, methyl, methyl sulphonyl or cyanic acid;
R bFor-CH 3, carboxyl ,-F ,-Cl ,-Br ,-I ,-CF 3, cyclopropyl ,-OCH 3,-CO 2Me ,-NR cR d,-(CH 2)-NR cR d, R 3-S (O) m-, R 3-S (O) 2-NR e-, R 3-NR e-S (O) 2-,-NR f-C (O)-R e,-C (O) NR cR dOr morpholinyl;
Each R c, R dBe independently hydrogen ,-CH 3,-C (O) CH 3,-CH 2CN, C 1-4Alkoxy carbonyl, methoxycarbonyl-C 1-2Alkyl-, methoxycarbonyl-C 3Naphthenic base-or-(CH 2)-C (O)-NR eR f
Each R e, R fBe independently hydrogen or-CH 3
R 3Be hydrogen or C 1-4Alkyl, its each randomly by one or two-OCH 3Or oxo replaces.
9. the compound of claim 8 or its pharmacy acceptable salt, and wherein
Ring G is cyclopropyl or cyclobutyl.
10. the compound of claim 9 or its pharmacy acceptable salt, and wherein
Ring G is a cyclopropyl.
11. the compound of claim 10 or its pharmacy acceptable salt, and wherein
R cBe hydrogen or C 1-6Alkyl, and R dBe C 1-6Acyl group, cyanic acid-C 1-6Alkyl-, C 1-6Alkoxy carbonyl-C 0-3Alkyl-, C 1-6Alkoxy carbonyl C 3-10Naphthenic base or-(CH 2) n-C (O)-NR eR f
Each R e, R fBe hydrogen, C independently 1-6Alkyl.
12. the compound of claim 11 or its pharmacy acceptable salt, and wherein
Ar 2Be phenyl, pyrimidyl, furyl, thiazolyl or pyridyl, it is respectively randomly by one or two R bReplace;
R bFor-SO 2Me ,-I ,-Br ,-Cl ,-CF 3,-OMe ,-NMe 2,-CONHMe ,-SO 2NH 2
13. the compound of claim 12 or its pharmacy acceptable salt, and Ar wherein 2For
Figure FDA00001782728300061
14. the compound of claim 13 or its pharmacy acceptable salt, and wherein
R gFor
I) C 1-2Alkyl ,-CF 3, C 2Thiazolinyl, phenyl, C 1-4Alkoxyl group, carbocylic radical CH 2O-, carbocylic radical CH 2-,-CH 2OH, hydroxyl ,-CO 2C 1-4Alkyl or oxo;
Or
Ii) be methyl, vinyl ,-CF 3, phenyl ,-CH 2OH or hydroxyl.
15. compound, it is selected from:
Figure FDA00001782728300062
Figure FDA00001782728300071
Figure FDA00001782728300081
Figure FDA00001782728300091
Figure FDA00001782728300101
Figure FDA00001782728300111
Or its pharmacy acceptable salt.
16. pharmaceutical composition, it comprises pharmaceutically compound and one or more carrier and/or auxiliary agents pharmaceutically of the claim 1 of significant quantity.
17. a method of treating chronic inflammatory diseases, transformation reactions, contact dermatitis, psoriasis, rheumatoid arthritis, multiple sclerosis, type i diabetes, inflammatory bowel, Guillain-Barre syndrome, Crohn disease, ulcerative colitis, graft versus host disease, Alzheimer, asthma, chronic nephropathy, Sepsis, autoimmune myocarditis and systemic lupus erythematous, it comprises the compound of the claim 1 that gives patient's pharmacy effective dose.
18. the method for claim 17, wherein said treatment is to rheumatoid arthritis and multiple sclerosis.
19. the method for claim 17, wherein said treatment is to rheumatoid arthritis.
20. the method for claim 17, wherein said treatment is to multiple sclerosis.
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